The guanosine triphosphate (GTP)-binding proteins include signal-transducing heterotrimeric G proteins (for example, Gs, Gi), smaller GTP-binding proteins that function in protein sorting, and the oncogenic protein p21ras. The T cell receptor complexes CD4-p56lck and CD8-p56lck were found to include a 32- to 33-kilodalton phosphoprotein (p32) that was recognized by an antiserum to a consensus GTP-binding region in G proteins. Immunoprecipitated CD4 and CD8 complexes bound GTP and hydrolyzed it to guanosine diphosphate (GDP). The p32 protein was covalently linked to [alpha-32P]GTP by ultraviolet photoaffinity labeling. These results demonstrate an interaction between T cell receptor complexes and an intracellular GTP-binding protein. ...
2P5E: Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry
The fine specificity of T cell recognition of peptide analogues of the influenza nucleoprotein epitope, NP 383-391 SRYWAIRTR, was studied using HLA B27-restricted influenza-specific cytotoxic T cell (CTL) clones, of defined T cell receptor (TcR) usage, derived from unrelated individuals following natural infection. Even conservative amino acid substitutions of the peptide residues P4, P7 and P8 influenced CTL recognition. These side chains are probably directly contacted by the TcR. CTL clones which used the TcR V alpha 14 gene segment (but not those using TcR V alpha 12) were also sensitive to P1 substitutions, suggesting that the TcR alpha chain of these clones lies over the N terminus of bound peptide, and that the footprint of certain TcR can span all exposed residues of a peptide bound to a major histocompatibility complex class I molecule. These results, taken together with previous structural and functional data, suggest that, for nonamer peptides bound to HLA B27, P1, P4 and P8 are flag
1OSZ: Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands.
The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCR gamma delta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell ...
Interest in the role of CD5 in lymphocyte development has grown considerably in light of recent data suggesting that CD5 functions to negatively regulate signaling through the B and T cell antigen receptors ((16), (17)). In this study, we examined CD5 expression during normal thymocyte development and in mice with defects in thymocyte maturation. Our results demonstrate a critical role for pre-TCR and TCR signals, and notably TCR avidity, in regulating CD5 surface expression.. Early DN thymocytes express very low levels of CD5 independent of their ability to undergo TCR gene rearrangement, and therefore independent of their ability to express pre-TCR and/or TCR complexes. That the pre-TCR is not required for initial CD5 expression on early DN thymocytes is not surprising, as previous studies have documented very low levels of CD5 on pro-T cells in the thymus ((46)). Of significance, however, is that signals transduced by the pre-TCR upregulate CD5, and that the level of CD5 surface expression ...
In this study, we have shown that bivalent anti-CD3 delivers a partial TCR signal that renders Th1 clones hyporesponsive. This signal consists of phosphorylation of several components of the TCR complex, (bands representing CD3ε, CD3δ), ZAP-70 association, and partial phosphorylation of TCR ζ; in the absence of cross-linking, there is a relatively greater induction of the phosphorylated p21 ζ as compared with the p23 ζ band species evident in T cell clones. Presently, it is unclear what the p21 and p23 forms of ζ represent. p21 induction appears to be sufficient for association of the ZAP-70 kinase with the TCR complex, whereas p23 induction and ZAP-70 phosphorylation appear to be interrelated events. Indeed, the low level of ZAP-70 phosphorylation observed in the noncross-linked situation correlates with the small amount of p23 ζ that is generated. In a recent study, Weist et al. ((28)) proposed that the p23 form of ζ observed in thymocytes upon in vitro stimulation depends on greater ...
Our study demonstrates for the first time that treatment with RTL after onset of MCAO reduces cortical and total infarct size, inhibits infiltrating inflammatory cells, particularly activated macrophages/microglial cells and DCs, into postischemic brain, and partially preserves spleen cell numbers that are typically ablated after MCAO. This result was specific to RTL551 treatment in C57BL/6 male mice and verified using a "humanized" RTL1000 construct to treat MCAO in HLA-DR2-Tg mice. The results clearly show that the therapeutic activity of RTL requires a neuroantigen peptide (mouse or human MOG-35-55) tethered to an MHC moiety that closely matches the Class II of the treated mouse strain (I-Ab for C57BL/6 mice and HLA-DR2 for DR2-Tg mice). In contrast, treatment of C57BL/6 mice with RTL553 comprised of I-Ab coupled to I-Ea-52-68 (a nonneuroantigen peptide) and RTL342M comprised of HLA-DR2 (nonmatched MHC Class II) coupled to mMOG-35-55 peptide did not have therapeutic effects.. Beyond the ...
The prevailing view of thymocyte selection is that the fate of developing cells is dictated exclusively by the affinity/avidity of the expressed TCR for self-MHC/self-ligand. We hypothesize that there is significant plasticity in the signaling processes that control T cell development and that the ability to fine-tune the TCR signaling response, through the regulated expression of molecules that positively or negatively impact the TCR signaling response operates to maximize the TCR repertoire. One example of a fine-tuning molecule that was previously characterized is the cell surface protein CD5. We found that CD5 is an inhibitory tuning receptor, and its surface expression is directly and proportionately regulated by the affinity of the TCR for selecting ligand. In order to identify additional candidates for TCR-tuning, we employed a TCR transgenic experimental system where TCR expression was fixed on all developing thymocytes and where the affinity of the positively selecting ...
The human T cell receptor for antigen (Ti) has recently been identified on IL-2 dependent T cell clones as a 90 kd disulfide-linked heterodimer comprised of one 49-51 kd alpha (alpha) and one 43 kd beta (beta) chain. These subunits are noncovalently associated with a monomorphic 20-25 kd T3 molecule. Here, we produce monoclonal antibodies to a human tumor (REX) derived from an earlier stage of thymic differentiation in order to determine whether clonotypic structures are expressed and to define the ontogeny of Ti. The results of SDS-PAGE and peptide map analyses indicate that an homologous T3-associated heterodimer is synthesized and expressed by REX. This glycoprotein shares several peptides in common with clonotypic structures on an IL-2 dependent T cell clone. In addition, similar Ti related molecules appear during intrathymic ontogeny in parallel with surface T3 expression. The latter findings provide the structural basis for the immunological competence observed exclusively within the T3+ thymocyte
Patients who were previously treated with Adaptimmune NY-ESO-1ᶜ²⁵⁹T cells are asked to take part in this study to see how safe NY-ESO-1ᶜ²⁵⁹T cells are and what
T lymphocytes are essential for the functioning of the adaptive immune system. This is demonstrated by genetic or virus induced human immunodeficiencies resulting from a lack of T-cells. T-cells recognize changes in their environment through a specific T-cell receptor (TCR) protein expressed on their surface. This receptor binds to peptide antigens presented in the context of major histocompatibility complex (MHC) proteins on the surface of antigen presenting cells. TCR binding to its ligand causes signaling that re-programs the cell by turning on new genes. TCR first gets expressed on the surface of T cell precursors that also have two co-receptors on their surface named CD4 and CD8. These double positive (DP) thymocytes have the business of generating all the T lymphocytes in the body. Re-programming by new gene expression is important for the development of the thymocyte precursors of T cells in the thymus and for the response of T lymphocytes in peripheral lymphoid organs. We are interested ...
In the absence of foreign antigen, peripheral naive T cells continuously recirculate between different lymphoid organs, in which they interact frequently and shortly with self. We and others have shown that such interactions are required for the long-term survival of naïve T cells. In addition, these TCR/MHC interactions and the resulting associated signaling increase quantitatively T-cell responsiveness towards foreign antigens and influence their function and/or differentiation into effector or memory cells in response to stimulation. Our project is based on our recent data showing that peripheral ab and gd T cells can be subdivided into various subsets according to Ly-6C expression. Interestingly, in CD4 ab T cells, Ly-6C expression inversely correlates with the ability of these cells to interact with self, defining Ly-6C as a new sensor of T cell self-reactivity. In parallel, we are exploring the regulation of T-cell self-reactivity in the context of cancer. Indeed, T cells specific for ...
J Immunol 172:4709-4716, 2004. PMID: 15067046. Cascalho M, Platt JL. B cell-dependent T cell development. Acta Paediatr 93(Supplement 445):52-53, 2004. PMID: 15176721. Cascalho M, Platt JL. B cells and B cell products-helping to restore cellular immunity? Transfus Med Hemother 33:45-49, 2006. PMID: 16755301. Balin SJ, Cascalho M. The rate of mutation of a single gene. Nucleic Acids Res. 2010. 38:1575-82. PMID: 20007603 3. Fitness of cellular immunity and T cell receptor diversity. T cell diversity is generally thought to confer immune fitness. However which properties of immunity depend absolutely on TCR receptor diversity and the extent of diversity necessary for optimal function are not fully understood. My research conducted in collaboration with Dr. Platt revealed for the first time that significant contractions of the T cell receptor repertoire do not impair certain functions of cell-mediated immunity, such as defense against intracellular fungi and rejection of grafts disparate for minor ...
T lymphocytes are essential for the functioning of the adaptive immune system. This is demonstrated by genetic or virus induced human immunodeficiencies resulting from a lack of T-cells. T-cells recognize changes in their environment through a specific T-cell receptor (TCR) protein expressed on their surface. This receptor binds to peptide antigens presented in the context of major histocompatibility complex (MHC) proteins on the surface of antigen presenting cells. TCR binding to its ligand causes signaling that re-programs the cell by turning on new genes. TCR first gets expressed on the surface of T cell precursors that also have two co-receptors on their surface named CD4 and CD8. These double positive (DP) thymocytes have the business of generating all the T lymphocytes in the body. Re-programming by new gene expression is important for the development of the thymocyte precursors of T cells in the thymus and for the response of T lymphocytes in peripheral lymphoid organs. We are interested ...
A type of T cell apoptosis that occurs towards the end of the expansion phase following the initial activation of mature T cells by antigen and is triggered by T cell receptor stimulation and signals transmitted via various surface-expressed members of th…
Results High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. ...
There is considerable controversy about the mechanism of T cell receptor (TCR) triggering, the process by which the TCR tranduces signals across the plasma membrane after binding to its ligand (an agonist peptide complexed with an MHC molecule). Three main types of mechanism have been proposed, which involve aggregation, conformational change and segregation. Here, we review recently published evidence for each type of mechanism and conclude that all three may be involved. This complexity may reflect the uniquely demanding nature of TCR-mediated antigen recognition, which requires the detection of a very weak signal (very rare foreign peptide-MHC ligands) in the presence of considerable noise (abundant self peptide-MHC molecules).
CHO-Anti-Human T-cell receptor F(ab) stable cell line is clonally-derived from a CHO cell line, which has been transfected with an anti-human T-cell receptor F(ab) gene to allow expression of the F(ab). It is an example of a cell line transfected using our proprietary CBTGS gene screening and amplification system.
1. The regulation of the immune response: vaccine design, phage-based vaccines, Virus-like-particle vaccines, protein vaccines, Alzheimers Disease immunotherapy, induction of immune responses to self-antigens, correlates of vaccine efficacy, signaling in T cell development and activation, T cell receptor repertoire in Coeliac disease, T cell receptor repertoire of antigen-specific T cell lines ...
Tumour necrosis factor family. Family of cytokines that form homotrimeric or heterotrimeric complexes. TNF mediates mature T-cell receptor-induced apoptosis through the p75 TNF receptor. ...
We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several dis...
T Cell Receptor (TCR) V beta 4, 0.125 mg. The receptors on T cells consist of immunoglobulin like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human.
To pursue our first goal, we have focused on developing advanced imaging techniques to understand the molecular interactions that underlie the process by which a particular T cell recognizes fragments of an antigen (peptide) that are bound to molecules of the major histocompatibility complex (MHC) and displayed on the surfaces of cells. These peptide-MHC complexes are then recognized by the T cell antigen receptor (TCR), an antibody-like molecule present on most T cells. The TCR is closely associated with the CD3 polypeptides, which mediate intracellular signaling through a kinase cascade. Our previous work and that of others characterized the biochemistry and genetics of TCRs, but in recent years we have focused on how these molecules operate in the larger context of T cell recognition, a context that includes other molecules on the T cell surface that work with the TCR, and on how ligand binding triggers T cell activation. Video microscopy and other advanced imaging techniques, such as ...
We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several dis...
CRE-mediated transcriptional activation is involved in cAMP protection of T-cell receptor-induced apoptosis but not in cAMP potentiation of glucocorticoid-mediated programmed cell death ...
Clone REA651 recognizes the mouse V beta 10 T cell receptor (TCR Vβ10). The T cell receptor is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. It is a disulfide-linked membrane-anchored heterodimeric glycoprotein normally consisting of the highly variable alpha and beta chains expressed as part of a complex with the invariant CD3 chain molecules. The α and β TCR chains are composed of constant and variable regions, each encoded by distinct gene segments. TCR Vβ10 is a variant of the TCR β chain and is expressed on T cells having the a haplotype, but not with the b and c haplotype of the TCRβ gene complex. Additional information: Clone REA651 displays negligible binding to Fc receptors. - Lëtzebuerg
T Cell Receptor (TCR) V beta-2, 0.1 mg. The receptors on T cells consist of immunoglobulin like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human.
It is not yet clear which are the activation signals underpinning this large expansion of polyclonal γδ T cells in this process. Proliferation was dependent on CD137L, IL2, and IL21, but the involvement of TCR signaling has not been tested. Although it is hard to conceive that aAPCs express the full array of TCR ligands for all expanded γδ T cells, engagement of TCR is suggested by the low TCR expression on generated Vδ2pos T cells and by the importance of CD137L for the expansion despite the absence of CD137 expression by γδ T cells prior expansion. Fisher and colleagues who coated B1 anti-γδTCR antibody on aAPCs showed it did not have a major role in γδ T-cell expansion even if this led to a better representation of Vδ2neg subsets. Gamma delta T cells have been shown to express HLA-I inhibitory receptors (7), so the absence of HLA-I expression by K562 as well as expression of activatory molecules such as NKG2D ligands may also play critical role in γδ T-cell activation.. Most ...
A trapped bead (right) decorated with a foreign antigen is actively placed on a T cell (left) and force is applied to facilitate recognition by the T cell receptor complex.
The Koelle lab will comprehensively define the CD4 and CD8 T cell epitopes in HSV-1 and HSV-2, using blood, skin lesion biopsy, eye, and brain samples, and using both culture-dependent and culture-independent methods based on T cell receptor sequencing and reconstruction.. ...
The Koelle lab will comprehensively define the CD4 and CD8 T cell epitopes in HSV-1 and HSV-2, using blood, skin lesion biopsy, eye, and brain samples, and using both culture-dependent and culture-independent methods based on T cell receptor sequencing and reconstruction.. ...
Researchers at National Jewish Health have answered a long-standing question about how the immune system selects T cells that recognize and attack potentially harmful invaders, while leaving alone a bodys own tissues.
(ID:13403) We have successfully demonstrated that the transmembrane adaptor SIT inhibits TCR-mediated signals required for i thymo
Cell surface receptor for NECTIN2. May act as a coinhibitory receptor that suppresses T-cell receptor-mediated signals. Following interaction with NECTIN2, inhibits T-cell proliferation. Competes with CD226 for NECTIN2-binding ...
Although cloning and expression of T-cell Receptors (TcRs) has been performed for almost two decades, these procedures are still challenging. For example, the use of T-cell clones that have undergone limited expansion as ...
Immune systems of vertebrates function via two types of effector cells, B and T cells, which are capable of antigen-specific recognition. The immunoglobulins, which serve as antigen receptors on B cells, have been well characterized with respect to gene structure, unlike the T-cell receptors. Recently, cDNA clones thought to correspond to the beta-chain locus of the human and mouse T-cell receptor have been described. The presumptive beta-chain clones detect gene rearrangement specifically in T-cell DNA and show homology with immunoglobulin light chains. The similarity of the T-cell beta-chain gene system to the immunoglobulin genes has been further demonstrated by the recent observation of variable- and constant-region gene segments as well as joining segments and putative diversity segments. We report here the characterization of cDNA and genomic clones encoding human T-cell receptor beta-chain genes. There are two constant-region genes (C beta 1 and C beta 2), each capable of rearrangement and
Immunological synapses are organized cell-cell junctions between T lymphocytes and APCs composed of an adhesion ring, the peripheral supramolecular activation cluster (pSMAC), and a central T cell receptor cluster, the central supramolecular activation cluster (cSMAC). In CD8(+) cytotoxic T lymphocytes, the immunological synapse is thought to facilitate specific killing by confining cytotoxic agents to the synaptic cleft. We have investigated the interaction of human CTLs and helper T cells with supported planar bilayers containing ICAM-1. This artificial substrate provides identical ligands to CD4(+) and CD8(+) T cells, allowing a quantitative comparison. We found that cytotoxic T lymphocytes form a ring junction similar to a pSMAC in response to high surface densities of ICAM-1 in the planar bilayer. MICA, a ligand for NKG2D, facilitated the ring junction formation at lower surface densities of ICAM-1. ICAM-1 and MICA are upregulated in tissues by inflammation- and stress-associated signaling,
Immunological synapses are organized cell-cell junctions between T lymphocytes and APCs composed of an adhesion ring, the peripheral supramolecular activation cluster (pSMAC), and a central T cell receptor cluster, the central supramolecular activation cluster (cSMAC). In CD8+ cytotoxic T lymphocytes, the immunological synapse is thought to facilitate specific killing by confining cytotoxic agents to the synaptic cleft. We have investigated the interaction of human CTLs and helper T cells with supported planar bilayers containing ICAM-1. This artificial substrate provides identical ligands to CD4+ and CD8+ T cells, allowing a quantitative comparison. We found that cytotoxic T lymphocytes form a ring junction similar to a pSMAC in response to high surface densities of ICAM-1 in the planar bilayer. MICA, a ligand for NKG2D, facilitated the ring junction formation at lower surface densities of ICAM-1. ICAM-1 and MICA are upregulated in tissues by inflammation- and stress-associated signaling, ...
Thymic selection of natural killer-1+ natural T cells that express alpha beta T cell receptors requires a conserved beta 2-microglobulin-associated molecule, presumably CD1d, displayed by CD4+8+ thymocytes. Here we demonstrate that positive selection of natural T cells occurs independent of transporters associated with antigen presentation-1 (TAP-1) function. Moreover, natural T cells in TAP-1o/o mice are numerically expanded. Several H-2 class Ib molecules function in a TAP-independent manner, suggesting that if expressed in TAP-1o/o thymocytes, they could play a role in natural T cell development. Of these class Ib molecules, H-2TL is expressed by TAP-1o/o thymocytes. Moreover, we find that thymi of TL+ mice congenic or transgenic for H-2T18 also have a numerically expanded natural T cell repertoire compared with TL- mice. This expansion, as in TAP-1o/o thymi, is evident in each of the limited T cell receptor V beta chains expressed by natural T cells, suggesting that TL and CD1d impact ...
Guanine nucleotide exchange factor (GEF) for RAB35 that acts as a regulator of T-cell receptor (TCR) internalization in TH2 cells (PubMed:20154091, PubMed:20937701, PubMed:24520163, PubMed:26774822). Acts by promoting the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form (PubMed:20154091, PubMed:20937701). Plays a role in clathrin-mediated endocytosis (PubMed:20154091). Controls cytokine production in TH2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes: acts by mediating clathrin-mediated endocytosis of TCR via its interaction with the adapter protein complex 2 (AP-2) and GEF activity (PubMed:26774822). Dysregulation leads to impaired TCR down-modulation and recycling, affecting cytokine production in TH2 cells (PubMed:26774822 ...
T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity. Total RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age-matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci. Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P |0.0002), a more uneven distribution of the
T cell receptor antigen complex. Molecular model of the alphabeta T cell receptor bound to the influenza haemagglutinin antigen and MHC class II molecule HLA-DR1. T cell receptors are protein complexes found on the surface of a type of white blood cell called T lymphocytes (or T cells), part of the bodys immune system. Antigens (foreign proteins) are presented to T cell receptors by MHC molecules to effect an immune response. - Stock Image C025/1593
This study investigated whether fingolimod reduced newly produced T and B lymphocytes and T-cell receptor repertoire diversity in peripheral blood in patients
To explore the possibility of an alternative strategy to treat hematological malignancies of HLA-A2+ HA-2-expressing patients transplanted with HLA-A2− donors, we isolated CMV-specific T cells from an HLA-A2− individual and transferred these T cells with HA-2-TCRs. For this purpose CMV-specific HLA-B7-restricted T cells (CMVB7-specific T cells) were FACS® sorted using CMVB7 tetramers stimulated with CMVB7 peptide-loaded, irradiated autologous PBMCs and transduced with the HA-2-TCR derived from the HA-2-specific T cell clone HA2.5, or with control retroviral vectors. By FACS® analyses we demonstrated that a high percentage of CMVB7-specific T cells was transduced (49-58%) and that the majority of HA-2-TCR α and β chain transduced T cells stained with the HA-2A2 tetramer (Fig. 6). Similar to the HA-2-TCR-transduced CMVA2-specific T cells, the CMVB7 tetramer staining was decreased on the HA-2-TCR-transduced CMVB7-specific T cells compared with the control-transduced CMVB7-specific T cells. ...
Adoptive T cell immunotherapy has shown promise in treating some cancers, but the challenge of isolating T cells with high avidity for tumor antigens limits large-scale applicability. T cell receptor (TCR) gene transfer employing high affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent these challenges. Using a well-characterized murine model of adoptive T cell immunotherapy for established malignancy, we have demonstrated the feasibility of eliminating disseminated leukemia using T cells genetically modified by TCR gene transfer.We next examined the potential of targeting a clinically relevant tumor antigen, the transcription factor WT1, for which the expression patterns in normal and malignant cells are similar in mouse and man. WT1 is overexpressed in most leukemias and many solid tumors and its expression contributes to the malignant phenotype. The RMFPNAPYL peptide from WT1 is presented by HLA-A2 in humans, as well as by H-2Db in C57BL/6 mice, and has been ...
Recognition by CD8,sup,+,/sup, cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that beta,sub,1,/sub, and beta,sub,3,/sub, integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC.peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling ...
Alterations in peptide ligand that result in better or worse binding to MHC are effectively a change in concentration of pMHC ligand. This becomes especially significant in in vivo settings, where encounter with Ag is usually more rare. When comparing different peptide ligands, careful determination of MHC binding is obviously essential prior to making conclusions as to the effect of various ligands upon TCR-pMHC interactions.. The rate at which TCR and pMHC associate (kon) and dissociate (koff) is shown. The t1/2 of the TCR-pMHC interaction is related to the off-rate koff by the equation t1/2 = ln 2/koff. Thus, shorter TCR-pMHC interactions have shorter t1/2 and faster off-rates relative to longer TCR-pMHC interactions. In equilibrium conditions, the affinity is calculated from koff/kon, which can be derived from surface plasmon resonance measurements. The t1/2 of TCR-pMHC interactions can also be measured by dissociation of fluorescently labeled pMHC tetramers (11), and the off-rates ...
After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively. The two latter proteins have been suggested to serve as substrates for ZAP-70 and to fine-tune its function. To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution at position 292 (Y292F) or 315 (Y315F). When analyzed in a sensitized TCR transgenic background, the ZAP-70 Y315F mutation reduced the rate of positive selection and delayed the occurrence of negative selection. Furthermore, this mutation unexpectedly affected the constitutive levels of the CD3-zeta p21 phosphoisoform. Conversely, the ZAP-70 Y292F mutation upregulated proximal events in TCR signaling and allowed more T cells to produce interleukin 2 and interferon gamma in response ...
The rupture forces and adhesion frequencies of single recognition complexes between an affinity selected peptide/MHC complex and a TCR at a murine hybridoma surface were measured using Atomic Force Microscopy. When the CD8 coreceptor is absent, the adhesion frequency depends on the nature of the peptide but the rupture force does not. When CD8 is present, no effect of the nature of the peptide is observed. CD8 is proposed to act as a time and distance lock, enabling the shorter TCR molecule to bridge the pMHC and have time to finely read the peptide. Ultimately, such experiments could help the dissection of the sequential steps by which the TCR reads the peptide/MHC complex in order to control T cell activation.
The interaction between a T cell and an antigen-presenting cell (APC) can trigger a signaling response that leads to T cell activation. Prior studies have shown that ligation of the T cell receptor (TCR) triggers a signaling cascade that proceeds through the coalescence of TCR and various signaling molecules (e.g., the kinase Lck and adaptor protein LAT [linker for T cell activation]) into microdomains on the plasma membrane. In this study, we investigated another ligand-receptor interaction (CD58-CD2) that facilities T cell activation using a model system consisting of Jurkat T cells interacting with a planar lipid bilayer that mimics an APC. We show that the binding of CD58 to CD2, in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. When simultaneously activated, TCR and CD2 initially colocalize in small microdomains but then partition into separate zones; this ...
Self-reactive CD4 T cells are thought to have a central role in the pathogenesis of many chronic inflammatory human diseases. Microbial peptides can activate self-reactive T cells, but the structural basis for such crossreactivity is not well understood. The Hy.1B11 T cell receptor (TCR) originates from a patient with multiple sclerosis and recognizes the self-antigen myelin basic protein. Here we report the structural mechanism of TCR crossreactivity with two distinct peptides from human pathogens. The structures show that a single TCR residue (CDR3α F95) makes the majority of contacts with the self-peptide and both microbial peptides (66.7-80.6%) due to a highly tilted TCR-binding topology on the peptide-MHC surface. Further, a neighbouring residue located on the same TCR loop (CDR3α E98) forms an energetically critical interaction with the MHC molecule. These data show how binding by a self-reactive TCR favors crossreactivity between self and microbial antigens.
ABSTRACT. Novel aspects of T cells containing TCRVβ20-1 are numerous, ranging from pathogen specific reactivity to specific tissue homing, or possible T cell subsets. Recently, it was demonstrated that TCR itself could become reactive by binding to small molecules free of the pHLA interface. Our work here was to identify a natural ligand binding to an identified pocket on the CDR2β loop of these TCR. Using docking of suspected ligands, we were able to show Guanine and Adenine diand tri-nucleotides readily bind to the identified site. Comparing these with small molecule sites found on other TCR types, we show this interaction is novel. With further molecular dynamic simulations, these sites are shown to be plausible by conducting simple computational based solubility tests as cross validation. Combined with simple proliferative responses, the identified nucleotides are also shown to have functional consequences by inducing T cell proliferation for CD4/Vβ20-1 + T cells, while failing to induce ...
This research study is being carried out to study a new way to possibly treat HIV. T‐cells are one of the white blood cells used by the body to fight HIV. CD8 T‐cells are a type of T‐cell used by the body to detect and kill cells which have been infected by foreign viruses or organisms, including the HIV virus. CD8 T‐cells must identify the HIV virus in order to kill it. Because HIV is constantly changing the way it looks to the CD8 T‐cells, some of the HIV virus escapes detection and is not killed by the CD8 T‐cells.. This research study uses a T cell receptor (TCR) protein specific for HIV (SL9 TCR) and adds it to the CD8 T‐cells in the laboratory in order to help the CD8 T‐cells recognize the constantly changing HIV virus and make it able to fight HIV more efficiently. TCR stands for T cell receptor. TCRs are found on the surface of T cells and allow the T cells to recognize other cells. Laboratory studies have shown that when CD8 T‐cells are modified with SL9 TCRs, they ...
About ACTolog® T-cell therapy. The ACTolog® concept is based on the principle of endogenous T-cell therapy pioneered by Professor Cassian Yee, M.D. Unlike tumor-infiltrating lymphocytes, ACTolog® T-cell products are generated from peripheral blood cells with defined target selectivity. Utilizing its proprietary antigen discovery platform XPRESIDENT®, Immatics has created a warehouse of eight cancer targets. From this warehouse, the most suitable targets for each patients tumor are identified by analyzing the tumor biomarkers. Up to four personalized T-cell products are then activated and manufactured for each patient by isolation and enrichment of the patients endogenous T-cells in vitro. Billions of such activated and specific T-cells are then re-infused into the cancer patient to attack the tumor.. About ACTengine® T-cell therapy. The ACTengine® approach is based on genetically engineering a patients own T-cells to express an exogenous T-cell receptor (TCR) to recognize the cancer ...
In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles ...
Themis and T cell development. CD4+ and CD8+ T cells expressing αβ TCRs begin their development as double negative (DN; CD4-CD8-) precursor thymocytes (Figure 6). Differentiation proceeds through several stages known as DN1-4. Progression and expansion past DN3 (CD44-CD25+) requires surface expression of the product of a chromosomally rearranged TCRβ chain, which pairs with an invariant pre-TCRα chain and then forms a complex with a CD3 heterodimer (CD3εγ or CD3εδ; see the record for tumormouse) and a CD3 zeta (ζ) homodimer (see the record for allia) (14). This complex, known as the pre-TCR, produces a TCR-like signal that is necessary for continued survival as well as the expansion of cell numbers and continued differentiation to the double positive (DP; CD4+CD8+) stage; TCR-associated signaling is described in more detail, below (15;16). After TCRβ rearrangement, progression to the DP stage, and TCRα rearrangement, the yet immature TCRαβ+CD4+CD8+ thymocytes are then subjected to ...
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There is a huge diversity of T cell receptor sequences within an organism," Stubbington explained. "Almost every cell has a different sequence, so being able to look within individual cells is powerful. Also, single-cell approaches allow us to see the paired sequences from two separate chromosomes that make up the TCR in each cell." To Lönnberg, the value of single-cell analysis for TCR sequencing is the fact that T cell activation and differentiation occurs at the individual-cell level. "Using single-cell sequencing," he said, "we can pinpoint the exact sequences associated with a specific response, rather than simply measuring enrichment at the level of TCR gene segments." While there are several published methods to identify T cell receptors at the single-cell level, Stubbington pointed out the difference with applying TraCeR to C1 mRNA Seq: Theres no need to target specific TCR sequences. "You get them for free whenever you perform single-cell RNA seq, so it adds an extra dimension of ...
Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells ...
Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells ...
Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with ...
Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with ...
Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with ...
Dolton G, Lissina A, Skowera A, Ladell K, Tungatt K, Jones E, Kronenberg-Versteeg D, Akpovwa H, Pentier J, Holland C, Godkin A, Cole D, Neller M, Miles J, Sewell A. Comparison of peptide-major histocompatibility complex tetramers and dextramers for the identification of antigen-specific T-cells. Clin Exp Immunol, 2014, 177 (1).. Estorninho M, Gibson V, Kronenberg-Versteeg D, Ni C, Cerosaletti K, Peakman M. Tracking antigen-experienced CD4 T-cells via tandem deep and shallow T-cell receptor clonotyping. Journal of Immunology, 2013, 191 (11).. Leung R, Simmons A, Proitis P, Guntert A, Kronenberg D, Pritchard M, Tsolaki M, Mecocci P, Kloszwska I, Vellas B, Soininen H, Wahlund LO, Lovestone S. Inflammatory proteins in plasma are associated with severity of Alzheimers disease. PLOS One, 2013, 8 (6).. Knight RR, Kronenberg D, Zhao M, Huang GC, Bulek A, Woolridge L, Cole DK, Sewell AK, Peakman M, Skowera A. Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly ...
[102 Pages Report] Check for Discount on Global T Cell Antigen Gp39 Sales Market Report 2017 report by QYResearch Group. In this report, the global T Cell Antigen Gp39 market...
The adhesion and degranulation adaptor protein (ADAP) was initially identified as a molecular adapter that couples T cell receptor (TCR) stimulation to the avidity of integrins governing T cell adhesion. TCR stimulation promotes the formation of a multi-protein complex containing CARMA1, MALT1, and BCL-10, which through the association of ADAP, ultimately activates the NF-kappaB family of transcription factors. More recent experiments have shown that ADAP controls optimal T cell proliferation, cytokine production, and expression of the Bcl-2 family member Bcl-x(L), suggesting that ADAP regulates T cell activation by promoting antigen-dependent T cell-antigen presenting cell (APC) activation. At least three isoforms of ADAP are known to exist ...
We have shown that THEMIS is required to enact a TCR‐induced negative feedback mechanism that modulates signal transmission. Previous work revealed similar TCR‐induced negative feedback devices originating from the LAT:SLP‐76 complex, which were mediated by the adaptors DOK‐1/DOK‐2 or the kinase HPK1 (Dong et al, 2006; Di Bartolo et al, 2007). However, in contrast to THEMIS KO mice, HPK1 KO or DOK‐1/DOK‐2 double KO showed no detectable defect of T‐cell development (Shui et al, 2007; Yasuda et al, 2007). Thus, THEMIS is part of an as yet unique TCR‐induced regulatory mechanism critical to drive T‐cell development (Fu et al, 2013). We found that THEMIS is constitutively associated with SHP1 and SHP2 through the adaptor GRB2. THEMIS knock‐down in human T cells and Jurkat 1G4‐CD8 cells increased CD3‐ζ phosphorylation and downstream activation events. Because TCR ligation induces recruitment of THEMIS, via GRB2, onto LAT (Paster et al, 2013), we infer that THEMIS allows ...
1bd2: Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids.
The general goal of this laboratory is to elucidate the mechanism of activation, differentiation and function, and its regulation of T cells which play central roles in the regulation of immune responses and homeostasis. These include the regulation of immunological synapse, T cell receptor-induced signal transduction, co-stimulation regulation and signaling in T cell development. Particularly, the mechanism to induce autoimmune diseases and inflammations caused by aberrant regulation of T cell function and activation will be analyzed to aim to overcome the diseases.. ...
T cells engineered to express the α and β chains of antigen-specific T cell receptors (TCRs) have shown promise as a cancer immunotherapy treatment; however, durable responses have been limited by poor persistence of gene-modified T cells. Additionally, severe toxicities, including patient deaths, have occurred upon infusion of large numbers of TCR-modified T cells. To enhance T cell persistence while providing a safeguard against life-threatening toxicity, we developed a dual-switch αβ TCR platform that uses a rapamycin (Rap)-induced caspase-9 (iRC9) together with a rimiducid (Rim)-controlled activation switch, inducible MyD88/CD40 (iMC).. The αβ TCR sequence derived from an HLA-A2-restricted, PRAME-specific T cell clone was synthesized and placed in-frame with iMC, comprising signaling domains from MyD88 and CD40 fused to tandem Rim-binding mutant FKBP12v36 domains to generate the iMC-PRAME TCR. Caspase-9 was fused to FRB and wild-type FKBP12 domains and cloned in-frame with a selectable ...
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Dr. Lakshmi Balagopalan is interested in the molecular events that follow activation of T cells via the T cell antigen receptor (TCR). Dr. Balagopalan is particularly focused on LAT, a molecule that plays a central role in T cell activation downstream of the TCR by directly or indirectly recruiting kinases, effectors, and adaptors to facilitate signal transduction pathways.
Toshiki Ochi is the author of this article in the Journal of Visualized Experiments: Generating De Novo Antigen-specific Human T Cell Receptors by Retroviral Transduction of Centric Hemichain
B cells carry antigen-specific receptors in the form of surface-bound immunoglobulin, which has a uniform antigen-binding capacity for any one B cell. As the body has the potential to produce...
Fate mapping of T cells from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ l
(A) Time course of activation of TCR-β-associated kinase activity in TCR-β-stimulated NOD and B6 thymocytes. NOD and control B6 thymocytes (2 × 107 ce
Insights into the structure and movement of T cell surface proteins could lead to new ways to fight cancers, infections and other diseases.
Immunological synapses are initiated by signaling in discrete T cell antigen receptor microclusters and are important for the differentiation and effector functions of T cells. Synapse formation involves the orchestrated movement of microclusters toward the center of the contact area with the antigen-presenting cell. Microcluster movement is associated with centripetal actin flow, but the function of motor proteins is unknown. Here we show that myosin IIA was necessary for complete assembly and movement of T cell antigen receptor microclusters. In the absence of myosin IIA or its ATPase activity, T cell signaling was interrupted downstream of the kinase Lck and the synapse was destabilized. Thus, T cell antigen receptor signaling and the subsequent formation of immunological synapses are active processes dependent on myosin IIA.
The mechanism of T cell depletion during infection with the human immunodeficiency virus (HIV) is unclear. Examination of the repertoire of T cell receptor V (variable) regions in persons infected with HIV revealed the absence of a common set of V beta regions, whereas V alpha usage was normal. The lack of these V beta segments did not appear to correlate with opportunistic infections. The selective elimination of T cells that express a defined set of V beta sequences may indicate the presence of an HIV-encoded superantigen, similar to those encoded by the long terminal repeat of the mouse mammary tumor virus. ...
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Aim: To compare clonal T cell receptor γ (TCRγ) gene rearrangements in frozen and formalin-fixed paraffin wax-embedded (FFPE) tissue, using capillary electrophoresis for use in diagnostics, as T cell lymphomas may be difficult to diagnose by conventional methods.. Methods: The DNA for PCR was extracted from frozen and FFPE tissue, cell lines and blood. PCR primers Vγ1-8, Vγ9, Vγ10 or Vγ11 (5′ end labelled) combined with a mixture of JγP1/JγP/JγP2/Jγ2 (unlabelled) were used. Monoclonal cases were sequenced and clonality, reproducibility, sensitivity and specificity analyses were carried out.. Results: In all cases the molecular test was found to be in agreement with the histological diagnosis. Discrepancies were found between frozen and FFPE tissue in 18 of 56 (32%) tests. The method was highly reproducible. The sensitivity was found to be 0.5% for cell lines and 1% for patient specimens and the specificity 100%. The junctional region between the Vγ and Jγ segments was specific for ...
T cell activation by nonself peptide-major histocompatibility complex (MHC) antigenic complexes can be blocked by particular sequence variants in a process termed T cell receptor antagonism. The inhibition mechanism is not understood, although such variants are encountered in viral infections and may aid immune evasion. Here, we study the effect of antagonist peptides on immunological synapse formation by T cells. This cellular communication process features early integrin engagement and T cell motility arrest, referred to as the stop signal. We find that synapses formed on membranes presenting antagonist-agonist complexes display reduced MHC density, which leads to reduced T cell proliferation that is not overcome by the costimulatory ligands CD48 and B7-1. Most T cells fail to arrest and crawl slowly with a dense ICAM-1 crescent at the leading edge. Similar aberrant patterns of LFA-1/ICAM-1 engagement in live T-B couples correlate with reduced calcium flux and IL-2 secretion. Hence, antagonist
T cells are activated when their T-cell antigen receptors (TCRs) are triggered by interactions with antigen peptide-major histocompatibility complex (pMHC) proteins on antigen-presenting cell (APC) surfaces. T cells exhibit exquisite selectivity and sensitivity, and the physical basis for these attributes within the TCR signaling system has attracted much interest. A significant aspect of TCR triggering is the spatial assembly of receptors on multiple length scales. At the scale of the cell itself, TCRs are visibly transported towards the center of the T-cell-APC interface, and the resulting spatial patterns of TCRs and other molecules are called the immunological synapse (Monks et al., 1998; Grakoui et al., 1999). Physically interfering with these transport processes can induce detectable changes in T cell signaling, such as phosphorylation of immunoreceptor tyrosine-based activation motifs on the TCR complex and intracellular calcium flux (Mossman et al., 2005). On shorter time and length ...
TY - JOUR. T1 - A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes. AU - ONeill, H C. PY - 1993/4/1. Y1 - 1993/4/1. N2 - A murine radiation leukemia virus (RadLV) has been shown to induce in vitro proliferation of an unusual subset of lymphoid cells from spleen. They have the unusual property of expressing CD3/T-cell receptor alpha and beta chains (TCR-alpha beta) in the absence of other T-cell markers such as Thy-1, CD4, and CD8. Cell lines induced in two mouse strains with RadLV produced by the C6VL/1 thymoma all specifically utilize common V alpha 3 and V beta 8.2 variable region genes in the formation of a TCR structure. Each of these cell lines has now been found to express both class I and class II major histocompatibility antigens and the beta 2 integrin specific for spleen dendritic cells. Analysis of functional properties of these cells has revealed a subset that can ...
Adoptive transfer of polyclonal Epstein-Barr-virus (EBV)-specific T cell lines has been used as prophylaxis and therapy in patients with EBV-associated malignancies. This approach, however, is limited by the difficult expansion of polyclonal T cells directed mainly against dominant EBV antigens presented on EBV-transformed B cell lines (LCLs). Isolating EBV-specific T cell receptors (TCRs) for transduction of T cells is an alternative strategy to confer T cell immunity against EBV antigens including subdominant EBV antigens. In this study, we have used peptide-pulsed DCs to selectively expand EBV-specific CD4+ T cell clones against an EBNA2-derived epitope. Data suggested that peptide-pulsed DCs are particularly effective in stimulating T cells specific for subdominant EBV antigens. TCR genes from one of these clones as well as from two CD8+ T cell clones were identified by RACE PCR. TCR alpha and beta chains where then cloned into retroviral vectors for transduction of T cells to equip them ...
Upon activation, naive CD8 T cells undergo a program of proliferation and differentiation that results in the acquisition of effector functions. Optimal T cell activation requires the integration of multiple signals including cross-linking of the T cell receptor (signal 1), co-stimulation (signal 2) and soluble factors such as cytokines (signal 3). Once a CD8 T cell has received these three signals they differentiate into an effector cell, which are able to control infection by directly killing the infected cell. Once the infection is cleared, these effector cells contract by controlled cell death and a long-lived population of memory cells remain. These potent memory cells are the defining feature of adaptive immunity as they offer protection for the life of the host due to their unique capabilities to survive in the absence of antigen and respond rapidly to secondary challenge. Therefore, effective CD8 T cell memory is the goal of cell-mediated vaccination strategies. While it is well ...
IN ADDITION, patients must satisfy the following Laboratory Criteria AND Clinical Criteria. Laboratory Criteria: (greater than or equal to 1 must be present). i. CD4+ lymphocytes: absolute number less than or equal to 50 percent of the lower limit of normal (LLN). ii. CD4 plus CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs)squared less than or equal to 5 percent of normal for age.. iii. Memory B Cells: absolute numberless than or equal to 50percent of LLN. iv. If serum IgM,normal for age. v. NK cells: absolute number less than or equal to 50 percent of LLN. vi. Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), is squared 25 percent with a normal control.. vii. Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks) in greater than or equal to 6 of the 24 V- Beta T-cell receptor families.. Clinical Criteria: (greater than or equal to 1 ...
ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Syk(hi)/ZAP-70(-) T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Syk(hi)/ZAP-70(-) T cells. However, Syk(hi)/ZAP-70(-) T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of ...
CC Grand Rounds (1) Treating Hematologic Malignancies with Chimeric Antigen Receptor T Cells and (2) Human Papilloma Virus (HPV)-Targeted T Cell Therapy for Patients with HPV-Associated Cancers
Comments, concepts and statistics about Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.
Material and methods Three DMARD-naïve ERA patients (disease duration , 1 year) and three ESRA patients (disease duration ,2 years) were included. All fulfilled the American College of Rheumatology1987 criteria for RA. mRNA was isolated from paired ST and PB samples. A linear amplification with primers for all V(ariable)-genes of the T cell receptor β-chain was performed. The amplified products contain the CDR3s of all T cells. Samples were processed using a Genome Sequencer (454) analysing up to 15 000 receptors per sample, The frequency of each clone was determined by its CDR3 frequency (% of all CDR3s analysed). Clones with a CDR3 frequency of ,1% were arbitrarily considered as highly expanded clones (HECs).. ...
General structure of Chimeric Antigen Receptor T tagged: molecular pathology, cancer, tcr, cd28, til, cancer immunotherapy, immunotherapy, tumor infiltrating lymphocytes, scfv, itam, immune response, cd3, powerpoint, slide
Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1-9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a ...
Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) ...
Title:Chimeric Antigen Receptor T Cell Based Immunotherapy for Cancer. VOLUME: 13 ISSUE: 5. Author(s):Feng Li, Tengfei Zhang, Ling Cao and Yi Zhang*. Affiliation:Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan. Keywords:Cancer immunotherapy, CAR T cells, hematologic malignancies, solid tumor, cancer cells, leukemia.. Abstract:Cancer immunotherapy, a new weapon against cancers by harnessing the patients own immune system, potentiates an extended remission and possibly a cure for cancer. T cells genetically engineered with chimeric antigen receptor (CAR) vectors can specifically target the surface antigen of cancer cells and kill them in an MHC-independent manner. CD19 is extensively ...
TY - JOUR. T1 - Single Antibody Detection of T-Cell Receptor αβ Clonality by Flow Cytometry Rapidly Identifies Mature T-Cell Neoplasms and Monotypic Small CD8-Positive Subsets of Uncertain Significance. AU - Shi, Min. AU - Jevremovic, Dragan. AU - Otteson, Gregory E.. AU - Timm, Michael M.. AU - Olteanu, Horatiu. AU - Horna, Pedro. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Background: The diagnosis of T-cell neoplasms is often challenging, due to overlapping features with reactive T-cells and limitations of currently available T-cell clonality assays. The description of an antibody specific for one of two mutually exclusive T-cell receptor (TCR) β-chain constant regions (TRBC1) provide an opportunity to facilitate the detection of clonal TCRαβ T-cells based on TRBC-restriction. Methods: Twenty patients with mature T-cell neoplasms and 44 patients without evidence of T-cell neoplasia were studied. Peripheral blood (51), bone marrow (10), and lymph node (3) specimens were evaluated by 9-color flow ...
Clinical trial for Lymphocytic Leukemia | Acute | Non-Hodgkins Lymphoma | B-Cell | Leukemia | B-Cell Lymphoma | Chronic | Chronic Lymphocytic Leukemia | childhood ALL | Lymphoma , CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies
TY - JOUR. T1 - T cell receptor α-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice. AU - Mao, Changchuin. AU - Osman, Gamal E.. AU - Adams, Sharlene. AU - Datta, Syamal K.. PY - 1994/2/1. Y1 - 1994/2/1. N2 - The production of pathogenic anti-DNA autoantibodies in mice with lupus nephritis is dependent on special autoimmune Th cells that can also transfer the disease into preautoimmune mice. In previous work, these pathogenic Th cells were cloned and their TCR β-chains were sequenced to reveal a recurrent motif of anionic residues in their CDR3 loops. Accordingly, approximately half of the Th clones were found to be specific for nucleosomal Ag that contain cationic residues. Herein, we analyzed the TCR α-chain repertoire of 15 of these pathogenic Th clones and found them to be heterogeneous, even among the nucleosome-specific Th clones. Most of these autoimmune TCR α-chains contained anionic residues in their CDR3 in addition to cationic residues. Therefore, these ...
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported