Cho, HI, et al. (2018) A novel Epstein-Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy. Br. J. Cancer. 2018 Jan 23;. PM ID: ...
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 ...
Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of
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 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
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 ...
Anti-isotypic reagents against the human T cell receptor (TcR) were made by immunizing rabbits with peptides which corresponded to sites within the co
Read independent reviews on MILLIPLEX® MAP 7-plex Human T Cell Receptor Signaling Kit - Phosphoprotein from MilliporeSigma on SelectScience
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…
The T-cell repertoire found in the periphery is thought to be shaped by two developmental events in the thymus that involve the antigen receptors of T lymphocytes. First, interactions between T cells and major histocompatibility complex (MHC) molecules select a T-cell repertoire skewed towards recog …
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).
We have established a system of TCRαβ ablation by combining the IFN-inducible Mx-Cre transgene with a loxP-flanked TCR Cα gene together with a TCRα null allele. pI/pC injection leads to the deletion of Cα in 40% of peripheral mature CD4+ and 80% of CD8+ cells. After about 10 days, the level of expression of the TCR complex on the surface of the Cα-deficient cells has declined by 2.5-3 orders of magnitude, as assessed by staining for TCRβ and CD3. Assuming that staining intensity is roughly proportional to the number of surface-bound TCR complexes, and that about 30,000 such complexes are expressed on mature T cells (26, 27), we conclude that no more than 100 TCR complexes could be expressed on the surface of the Cα-deficient cells 10 days after induction of Cα deletion. To our surprise, we found that, on the basis of liposome-assisted flow cytometric analysis, low levels of TCRβ chains, likely in the order of 100 molecules per cell when we take analogous data from the literature into ...
Construction of the T-cell receptor The antibody is not the only protein that recognizes the antigen. The antigen-specific receptor of T lymphocytes does the same. It is simply called the T-cell receptor and is abbreviated as the T-cell receptor TCR. We can define the antigen as a compound capable of eliciting the formation of a …. CELL IMMUNITY. T-CELL receptors (TCRs) and their epitopes Read More ». ...
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts ...
Mono-7D6-Fab co-potentiated TCR/CD3 signaling in response to weak pMHC antigens that possessed a critical minimal antigenic strength. Here, we present the main model of receptor co-potentiation by an otherwise intrinsically inert monovalent Fab (fig. S8). Ligation of TCR/CD3 by weak antigens induces weak signal transduction and weak T cell responses (fig. S8A). In contrast, ligation by anti-TCR/CD3 monovalent Fab is inert, inducing no classical signal transduction and producing no functional T cell response even though such Fab binding may induce biophysical alteration to the receptor (fig. S8B). The co-potentiation principle states that weak antigenic ligation plus intrinsically inert monovalent Fab ligation can synergize to enhance TCR signaling and T cell responses (fig. S8C).. The identification of specific properties displayed by Mono-7D6-Fab permitted an investigation of the co-potentiation concept. Mono-7D6-Fab did not impede pMHC:TCR interactions and did not intrinsically induce TCR/CD3 ...
TY - JOUR. T1 - The affinity of elongated membrane-tethered ligands determines potency of T cell receptor triggering. AU - Chen, Bing Mae. AU - Al-Aghbar, Mohammad Ameen. AU - Lee, Chien Hsin. AU - Chang, Tien Ching. AU - Su, Yu-Cheng. AU - Li, Ya Chen. AU - Chang, Shih En. AU - Chen, Chin Chuan. AU - Chung, Tsai Hua. AU - Liao, Yuan Chun. AU - Lee, Chau Hwang. AU - Roffler, Steve R.. PY - 2017/7/10. Y1 - 2017/7/10. N2 - T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I ...
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 ...
TY - JOUR. T1 - TCR clonotypes. T2 - molecular determinants of T-cell efficacy against HIV. AU - Lissina, Anya. AU - Chakrabarti, Lisa A. AU - Takiguchi, Masafumi. AU - Appay, Victor. PY - 2016/2. Y1 - 2016/2. N2 - Because of the enormous complexity and breadth of the overall HIV-specific CD8+ T-cell response, invaluable information regarding important aspects of T-cell efficacy against HIV can be sourced from studies performed on individual clonotypes. Data gathered from ex vivo and in vitro analyses of T-cell responses and viral evolution bring us one step closer towards deciphering the correlates of protection against HIV. HIV-responsive CD8+ T-cell populations are characterized by specific clonotypic immunodominance patterns and public TCRs. The TCR endows T-cells with two key features, important for the effective control of HIV: avidity and crossreactivity. While TCR avidity is a major determinant of CD8+ T-cell functional efficacy against the virus, crossreactivity towards wildtype and ...
T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as K D ~1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.
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.
What happens when T cells detect suspicious activity in the body? Researchers from the TU Wien and the Medical University of Vienna have revealed that immune receptors of T cells operate in unsuspected ways.
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.
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, ...
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 ...
Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of signaling motifs (ITAMs) in the CD3-zeta subunits of the TCR is an initial step in the transduction of signaling cascades. However, zeta phosphorylation is also promoted by ZAP-70, as TCR-induced zeta phosphorylation is defective in ZAP-70-deficient T cells. We show that this defect is corrected by stable expression of ZAP-70, but not Syk, in primary and transformed T cells. Indeed, these proteins are differentially coupled to the TCR with a 5- to 10-fold higher association of ZAP-70 with zeta as compared to Syk. Low-level Syk-zeta binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to zeta correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent zeta chain phosphorylation is promoted by ZAP-70 but ...
The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in Naxagolide normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation but are dispensable for memory CD8 T-cell persistence. Introduction Protection against recurrent infections resulting from the same pathogen is a hallmark of adaptive immunity. After acute infection by an intracellular pathogen naive CD8+ T cells expressing epitope-specific T-cell receptors (TCRs) are activated. The effector phase of the response is short with a rapid expansion of antigen-specific T cells and pathogen clearance. Rabbit ...
Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell …
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 development from immature CD4(+)CD8(+) double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal - from little-or-none, through intermediate, to strong - received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling.
The T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the α and β chains, and a signaling subunit, namely the CD3ε, γ and δ chains and the TCRζ chain. This complex participates in T-cell activation upon the presentation of the antigen peptide (derived from the foreign antigen) bound to the MHC (Class I and Class II) residing on antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells. Co-stimulatory receptors, such as CD2, CD28, CD4, CD8, and integrin molecules, contribute to signal transduction by modulating the response threshold. All the above components along with accessory proteins essential for MHC are a part of the immunological synapse that initiates T-cell activation. Protein tyrosine phosphorylation mediated by the Src family kinases Lck and Fyn, in turn regulated by CD45, is the initial event in TCR signaling. Lck is activated by the interaction of MHC and CD4 or CD8. It then induces the phosphorylation and activation of ...
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
Using H-2Kd-restricted CTL clones, which are specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS(252-260) (SYIPSAEKI) and permit assessment of TCR-ligand interactions by TCR photoaffinity labeling, we have previously identified several peptide derivative variants for which TCR-ligand binding and the efficiency of Ag recognition deviated by fivefold or more. Here we report that the functional CTL response (cytotoxicity and IFN-gamma production) correlated with the rate of TCR-ligand complex dissociation, but not the avidity of TCR-ligand binding. While peptide antagonists exhibited very rapid TCR-ligand complex dissociation, slightly slower dissociation was observed for strong agonists. Conversely and surprisingly, weak agonists typically displayed slower dissociation than the wild-type agonists. Acceleration of TCR-ligand complex dissociation by blocking CD8 participation in TCR-ligand binding increased the efficiency of Ag recognition in cases where
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. ...
We tested for antigen recognition and T cell receptor (TCR)-ligand binding 12 peptide derivative variants on seven H-2Kd-restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252-260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd-peptide derivative complexes allowed direct assessment of TCR-ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR-ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which antigen recognition was five-tenfold less efficient than TCR-ligand binding, (b) TCR antagonists (2 cases), which were not recognized and
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 ...
T-Cell Antigen Receptors: Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (ANTIGENS, CD3). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.
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.
Dive into the research topics of p21(ras) function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. Together they form a unique fingerprint. ...
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 ...
TY - JOUR. T1 - CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing invariant Vα24JαQT cell receptor α chains. AU - Exley, Mark. AU - Porcelli, Steven. AU - Furman, Margo. AU - Garcia, Jorge. AU - Balk, Steven. PY - 1998/9/7. Y1 - 1998/9/7. N2 - A population of human T cells expressing an invariant Vα24JαQ T cell antigen receptor (TCR) α chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. Unlike other CD161+ T cells, the major histocompatibility complex-like nonpolymorphic CD1d molecule is the target for the TCR expressed by these T cells (Vα24(invt) T cells) and by the homologous murine NK1 (NKR- P1C)+ T cell population. In this report, CD161 was shown to act as a specific costimulatory molecule for TCR-mediated proliferation and cytokine secretion by Mα24(invt) T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR ...
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.
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts ...
Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain-containing inositol polyphosphate 5-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.
One of the most well-known among these alternative types of immunotherapies is gene modified T cell receptor (TCR) therapy. In CAR-T therapy, naturally occurring T cells are engineered to express chimeric receptors on their cell surface. The external portion of these artificial receptors is made up of an antibody that directs the T cells to recognise specific cancer cells. Like CAR-T therapy, gene modified TCR therapy also works by redirecting T cells to target tumours. However, instead of engineering T cells to have artificial chimeric receptors, gene modified TCR therapy uses genetic modification to create T cells that contain a specific T cell receptor. Gene modified TCRs can recognise antigens that are present on the inside of cancer cells (and which are presented on the cell surface by the major histocompatibility complex (MHC)). In contrast, CAR-T cells can only recognise antigens that are expressed on the cell surface.. There are many researchers and companies exploring gene modified TCR ...
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 ...
Fingerprint Dive into the research topics of RNase H-dependent PCR-enabled T-cell receptor sequencing for highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and repertoire analysis. Together they form a unique fingerprint. ...
We record that individual T cells persistently contaminated with primate foamy pathogen type 1 (PFV-1) display an elevated capacity to bind individual immunodeficiency pathogen type 1 (HIV-1), leading to improved cell permissiveness to HIV-1 infection and improved cell-to-cell pathogen transmission. replication could be modulated by the current presence of either homologous faulty viral genomes or infections of specific classes with the capacity of interfering with particular levels of the pathogen routine in dually contaminated organisms. It really is set up that coinfection with various other retroviruses (individual T-cell leukemia pathogen types 1 and 2) (31), individual herpesviruses (individual herpesvirus type 6 [HHV-6], HHV-7, and HHV-8) (4, 7, 9, 12, 32), or non-pathogenic flavivirus GB pathogen (30) influences development of individual immunodeficiency pathogen type 1 (HIV-1) disease. Foamy infections (FVs) are innocuous complicated retroviruses that create lifelong persistent ...
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 ...
Anti-CD4 monoclonal antibodies are potential therapeutic agents for the prevention of autoimmune disease and treatment of rejection after organ transplantation and are capable of both restoring tolerance to self-antigens and inducing tolerance to antigens introduced under the cover of the antibody therapy in vivo. Tolerance to donor alloantigens can be induced in vivo by administering donor alloantigen in combination with either depleting (YTA 3.1) or nondepleting (YTS 177) anti-CD4, 28 days before heart transplantation in the mouse. The effect of anti-CD4 on proximal T-cell receptor (TCR) signalling pathways and proliferation was investigated in vitro and in vivo in the presence and absence of YTA 3.1 or YTS 177. Anti-CD4 was found to perturb proximal signalling events upon TCR/CD3 ligation, resulting in reduced tyrosine phosphorylation of Zap-70 and LAT (linker for activation of T cells) and reduced association of tyrosine-phosphorylated LAT with lck. This ultimately resulted in severely reduced
Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed ...
T-Cell Receptor Signaling Phospho-Specific Array includes 188 highly specific and well-characterized phosphorylation antibodies in the T-cell receptor signaling pathway. (AA0040) - Products - Abnova