TY - JOUR. T1 - Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. AU - King, Irah L.. AU - Fortier, Anne. AU - Tighe, Michael. AU - Dibble, John. AU - Watts, Gerald F.M.. AU - Veerapen, Natacha. AU - Haberman, Ann M.. AU - Besra, Gurdyal S.. AU - Mohrs, Markus. AU - Brenner, Michael B.. AU - Leadbetter, Elizabeth A.. PY - 2012/1/1. Y1 - 2012/1/1. N2 - Mouse invariant natural killer T cells (iNKT cells) provide cognate and noncognate help for lipid and protein-specific B cells, respectively. However, the long-term outcome for B cells after cognate help is provided by iNKT cells is unknown at present. Here we found that cognate iNKT cell help resulted in a B cell differentiation program characterized by extrafollicular plasmablasts, germinal-center formation, affinity maturation and a robust primary immunoglobulin G (IgG) antibody response that was uniquely dependent on iNKT cell-derived interleukin 21 (IL-21). However, cognate help ...

Background: Invariant natural killer cells (iNKT) are an important immunoregulatory T cell subset. Currently several flow cytometry-based approaches exist for the identifi-cation of iNKT cells, which rely on using the 6B11 monoclonal antibody or a combina-tion of anti-Vα24 and anti-Vβ11 antibodies. Objective: The aim of this study was to compare the ability of two flow cytometry-based methods for detecting the frequency of circulating iNKT cells. Methods: The frequency of iNKT cells was detected in the pe-ripheral blood of 37 healthy adult donors by flow cytometry using the 6B11 antibody or a combination of anti-Vα24 and anti-Vβ11 antibodies. Results: The frequency of iNKT cells detected by 6B11 antibody or by combination of anti-Vα24 and anti-Vβ11 anti-bodies was significantly different (0.54% vs. 0.31%, respectively, p|0.001) but the val-ues were highly correlated (Spearman r = 0.742, p|0.0001). Conclusion: The results of this study indicate that different combinations of mAbs detect different

Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to alpha-galactosylceramide (alpha-GalCer) and reduced iNKT cell-mediated lysis of wild-type targets loaded with alpha-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4(+) T cell responses were generally unaffected, processing of a lysosome-dependent analogue of alpha-GalCer was impaired in all the

TY - JOUR. T1 - Invariant Natural Killer T Cells Suppress the Neutrophil Inflammatory Response in a Mouse Model of Cholestatic Liver Damage. AU - Wintermeyer, Philip. AU - Cheng, Chao Wen. AU - Gehring, Stephan. AU - Hoffman, Beth L.. AU - Holub, Martin. AU - Brossay, Laurent. AU - Gregory, Stephen H.. PY - 2009/3. Y1 - 2009/3. N2 - Background & Aims: NK1.1+ TCRαβint CD1-restricted T (NKT) cells are a unique subset of T lymphocytes that are believed to have an immunoregulatory role in a wide range of diseases. Most mouse NKT cells express a T-cell receptor that contains an invariant Vα14Jα18 chain and recognizes antigenic glycolipids presented in association with major histocompatibility complex class Ib (CD1d) molecules. These invariant NKT (iNKT) cells have been implicated in cholestatic liver injury. Methods: We examined the role of iNKT cells in liver injury associated with biliary obstruction in mice with ligations of the common bile duct. Results: The number of activated iNKT cells ...

Immunoglobulin (Ig) M production can be induced by the interaction of thymus-independent type-2 (TI-2) antigen (Ag) with B cell Ag receptors (BCRs) without the involvement of conventional T cells; for IgG production through the same process, however, a second signal is required. Previous studies have reported that invariant natural killer T (iNKT) cells may be responsible for the second signal involved in IgG production. In the present study, we addressed whether human iNKT cells could participate in the production of Ig against TI-2 Ag in vitro. Two major distinct subsets of human iNKT cells, CD4+ CD8β- (CD4) and CD4- CD8β- [double negative (DN)] cells, were generated from peripheral blood monocytes from a healthy volunteer. BCR engagement, triggered by anti-IgM antibody stimulation, examined here as a model of BCR engagement triggered by TI-2 Ag, induced abundant IgM production by B cells. Both CD4 and DN iNKT cells reduced IgM production and conversely enhanced IgG production in a dose

Invariant natural killer T (iNKT) cells represent a unique population of CD1d-restricted T lymphocytes expressing an invariant T cell receptor (TCR) encoded by Vα14-Jα18 and Vα24-Jα18 gene segments in mice and humans, respectively. Recognition of CD1d-loaded endogenous lipid antigen(s) on CD4/CD8-double positive (DP) thymocytes is essential for the development of iNKT cells. The lipid repertoire of DP thymocytes and the identity of the decisive endogenous lipid ligands have not yet been fully elucidated. Glycosphingolipids (GSL) were implicated to serve as endogenous ligands. However, further in vivo investigations were hampered by early embryonal lethality of mice deficient for the key GSL-synthesizing enzyme glucosylceramide (GlcCer) synthase (GCS, EC 2.4.1.80). We have now analyzed the GSL composition of DP thymocytes and shown that GlcCer represented the sole neutral GSL and the acidic fraction was composed of gangliosides. Furthermore, we report on a mouse model that by combination of Vav

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally

Oesophageal adenocarcinoma (OAC) is an aggressive malignancy with poor prognosis, and incidence is increasing rapidly in the Western world. Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites and kill infected cells, yet their role in OAC is unknown. We aimed to elucidate the role of MAIT cells during cancer development by characterizing the frequency, phenotype, and function of MAIT cells in human blood and tissues, from OAC and its pre-malignant inflammatory condition Barretts oesophagus (BO). Blood and tissues were phenotyped by flow cytometry and conditioned media from explanted tissue was used to model the effects of the tumor microenvironment on MAIT cell function. Associations were assessed between MAIT cell frequency, circulating inflammatory markers, and clinical parameters to elucidate the role of MAIT cells in inflammation driven cancer. MAIT cells were decreased in BO and OAC blood compared to healthy controls, but were increased in oesophageal tissues, ...

The quest for new therapeutics and better follow-up of patients with inflammatory bowel diseases (IBD) requires the clearest possible picture of the immunological mechanisms underlying these complex pathologies. We identified recently a potential new player in this destructive game, a non-conventional T cell subset called Mucosal-Associated Invariant T (MAIT) cells. These cells were initially identified on the basis of their use of a semi-invariant TCR, made of the invariant V7.2-J33 TCR chain (now TCRAV1S2-AJ33) paired to a limited number of different TCR chains (1). Human MAIT cells are mostly CD8+ T cells with an effector/memory phenotype and expression of various chemokine receptors involved in extra-lymphoid migration. They also express most markers associated with IL-17 producing T cells, such as RORt, high CD161, IL-23R and CD26. They make up to 10% of peripheral blood and intestinal lamina propria T cells, and are even more abundant in the liver (2). The most striking feature of

In experimental crescentic GN, immature kidney DCs are protective13 until they mature, when inflammation becomes chronic.12 The underlying mechanisms remain to be elucidated. We speculated that, in this early phase, DCs might suppress harmful immune responses by recruiting anti-inflammatory leukocytes, and we addressed this hypothesis in NTN, a model of crescentic GN. When we depleted DCs in CD11c.LuciDTRmice with NTN, we noted that iNKT cells but not proinflammatory leukocytes were markedly reduced within the kidney. This finding sparked our interest, because two recent studies had shown a protective role for NKT cells in renal inflammation. Anti-GBM GN was aggravated in NKT cell-deficient CD1d knockout mice, and adoptively transferred NKT cells localized to the inflamed kidney and prevented this phenotype, which was astonishing, because NKT cells cannot recognize antigen in CD1d-deficient mice.18 Nevertheless, Mesnard et al.19 performed this experiment 1 year later in Jα18 knockout mice, ...

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T

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Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48-72h after activation. Together the data support the late effects of vitamin D on

Leukocyte cell-derived chemotaxin 2 (LECT2) was originally identified for its possible chemotactic activity against human neutrophils in vitro. It is a 16-kDa protein that is preferentially expressed in the liver. Its homologues have been widely identified in many vertebrates. Current evidence suggests that LECT2 may be a multifunctional protein like cytokines. However, the function of LECT2 in vivo remains unclear. To elucidate the role of this protein in vivo, we have generated LECT2-deficient (LECT2(-/-)) mice. We found that the proportion of NKT cells in the liver increased significantly in LECT2(-/-) mice, although those of conventional T cells, NK cells, and other cell types were comparable with those in wild-type mice. Consistent with increased hepatic NKT cell number, the production of IL-4 and IFN-gamma was augmented in LECT2(-/-) mice upon stimulation with alpha-galactosylceramide, which specifically activates Valpha14 NKT cells. In addition, NKT cell-mediated cytotoxic activity against

Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cell Therapy for Cancer Researchers developed a proof-of-concept for hematopoietic stem cell-engineered invariant natural killer T (iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patients lifetime. [Cell Stem Cell] Abstract , Graphical Abstract Follicular Regulatory T Cells Control Humoral and Allergic Immunity by Restraining Early B Cell Responses A follicular regulatory T (TFR) cell-deleter mouse was developed that selectively deletes TFR cells, facilitating temporal studies. TFR cells were found to regulate early, but not late, germinal center responses to control antigen-specific antibody and B cell memory. [Nat Immunol] Abstract Overcoming Adaptive Therapy Resistance in AML by Targeting Immune Response Pathways The authors identified activation of innate immune stress response pathways after treatment of FMS-like receptor tyrosine kinase (FLT3)-mutant acute myeloid leukemia ...

Background Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. Results We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4− NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells,

Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population involved in anti-bacterial immunity. In human beings, MAIT cells are abundant, comprising ~10% of the CD8(+) T-cell compartment in blood. They are enriched at mucosal sites and are particularly prevalent within the liver. MAIT cells are defined by the expression of a semi-invariant T-cell receptor (Vα7.2-Jα33/12/20) and are restricted by the non-polymorphic, highly evolutionarily conserved MHC class Ib molecule, MHC-related protein (MR)1. MR1 has recently been shown to present an unstable pyrimidine intermediate derived from a biosynthetic precursor of riboflavin; riboflavin biosynthesis occurs in many bacteria but not in human beings. Consistent with this, MAIT cells are responsive to riboflavin-metabolizing bacteria, including Salmonella. In mouse models, MAIT cells have been shown to play a non-redundant role in anti-bacterial immunity, including against Escherichia coli, Klebsiella pneumoniae, and Mycobacterium bovis

Background: NK (natural killer) and NKT (natural killer T) cells, as components of innate immune system, play a crucial role in tumor progression and dissemination. Objective: To investigate the percentages of NK cells, NKT cells, iNKT (invariant natural killer T) cells, total T lymphocytes as well as activated T lymphocytes, in tumor draining lymph nodes (TDLNs) of patients with breast cancer (BC) and their association with different clinic-pathological features of the patients. Methods: Axillary lymph nodes were obtained from 30 Iranian women with breast cancer. After routine pathological evaluations, mononuclear cells were separated from their lymph nodes and incubated with appropriate fluorochrome conjugated monoclonal antibodies specific for CD3, HLA-DR, CD16/56, and Vα24Jα18-TCR. Data were collected on a four-color flow cytometer and analyzed by CellQuest software. Results: The mean percentages of NK (CD3-CD16/56+), NKT (CD3+CD16/56+) and iNKT (Vα24Jα18-TCR+) cells in TDLNs mononuclear cells

A new study published by the Journal of Clinical Investigation has revealed that chronic inflammation is caused by obesity and alters the immune system and the gut microbial environment. The changes to the immune system consist of alterations to the mucosal-associated invariant T (MAIT) cells. MAIT cells are an innate-like T cell population that recognizes bacterial ligands and is enriched in mucosal and inflamed tissues. Obesity is associated with low-grade inflammation in fat tissue and dysfunctional fat cells produce inflammatory molecules. The fat tissue accumulation of immune cells such as macrophages, lymphocytes, neutrophils, and mast cells is a contributing factor in obesity and obesity-induced type 2 diabetes (T2D). In the fat tissue of lean people, the innate immune semi-invariant natural killer T (iNKT) cells are enriched in contrast to the fat tissue of obese patients. Mucosal-associated invariant T (MAIT) cells are a novel subset of innate-like immune cells found in peripheral ...

Humans have two populations of innate-like T lymphocytes with an invariant T cell antigen receptor (TCR) a chain: invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells. iNKT cell involvement in human asthma has been suggested, but is controversial, while there has been little analysis of MAIT cells. Using peripheral blood cells from the urban environment and childhood asthma (URECA) birth cohort study, we carried out a comprehensive investigation to determine if iNKT cell frequency or MAIT cell frequency early in life is correlated with the cytokine polarization of mainstream CD4+T cells and/or the development of asthma by age seven. We also determined if iNKT cell antigenic activity in house dust samples was associated with environmental endotoxin or clinical outcomes including aeroallergen sensitization and recurrent wheeze at 3 and asthma at age 7. We also analyzed the correlation between cytokines released by activated iNKT and MAIT cells and various ...

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell ...

To optimize vaccination strategies, it is important to use protocols that can jump-start immune responses by harnessing cells of the innate immune system to assist the expansion of antigen-specific B and T cells. In this Review, we discuss the evidence indicating that invariant natural killer T (iNKT) cells can positively modulate dendritic cells and B cells, and that their pharmacological activation in the presence of antigenic proteins can enhance antigen-specific B- and T-cell responses. In addition, we describe structural and kinetic analyses that assist in the design of optimal iNKT-cell agonists that could be used in the clinical setting as vaccine adjuvants.

Sexually transmitted infections (STIs) unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome

Human Vα24− CD1d-restricted T cells use variation in their CDR1α loop to respond to lipid antigens presented by CD1d, altering their specificities from that of invariant natural killer T cells.

Invariant NKT (iNKT) cells can prevent diabetes by inhibiting the differentiation of anti-islet T cells. We recently showed that neither iNKT cell protection against diabetes nor iNKT cell inhibition of T cell differentiation in vitro requires cytokines such as IL-4, IL-10, IL-13, and TGF-beta. In contrast, cell-cell contacts were required for iNKT cell inhibition of T cell differentiation in vitro. The present study was designed to determine whether the CD1d molecule is involved in the inhibitory function of iNKT cells. Experiments were performed in vitro and in vivo, using cells lacking CD1d expression. The in vivo experiments used CD1d-deficient mice that were either reconstituted with iNKT cells or expressed a CD1d transgene exclusively in the thymus. Both mouse models had functional iNKT cells in the periphery, even though CD1d was not expressed in peripheral tissues. Surprisingly, both in vitro inhibition of T cell differentiation by iNKT cells and mouse protection against diabetes by iNKT cells

Plasmalogen lysophosphatidylethanolamine (pLPE) had been identified as a self antigen for natural killer T cells (NKT cells). It is very important in the development, maturation and activation of NKT cells in thymus. Besides, pLPE is a novel type of antigen for NKT cells. To evaluate the structure-activity relationship (SAR) of this new antigen, pLPE and its analogues referred to different aliphatic chains and linkages at the sn-1 position of the glycerol backbone were synthesized, and the biological activities of these analogues was characterized. It is discovered that the linkages between phosphate and lipid moiety are not important for the antigens activities. The pLPE analogues 1, 3, 4, 7 and 9, which have additional double bonds on lipid parts, were identified as new NKT agonists. Moreover, the analogues 4, 7 and 9 were discovered as potent Th2 activators for NKT cells ...

To make their discovery, scientists infected three groups of mice with H1N1 flu virus. (Note: this is NOT the H5N1 flu virus that has been at the center of recent controversy.) The first group included normal mice; the second group was devoid of natural killer T cells, and the third was given a treatment that specifically activated natural killer T cells. Researchers observed the outcome of flu infection and found that the mice without natural killer T cells did worst, and those with activated killer T cells did best. Mice that lacked natural killer T cells had increased amounts of monocytes in the lungs, and severe lung injury similar to those seen in Spanish flu and lethal swine flu. Using highly-sensitive fluorescent antibody technology, this study was one of the first to document the sequential changes in innate immune response in the lungs during severe flu infection. These findings essentially provide a road map of the chronological changes in the lungs during severe flu infection. ...

Dr. Xiao-Ping Zhong or Dr. Jimin Gao, Duke University Medical Center, Durham, NC 27710 (X.-P.Z.) or School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China (J.G.). E-mail addresses: xiaoping.zhong{at}duke.edu (X.-P.Z.) or jimingao64{at}163.com (J.G ...

Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant Natural Killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the present study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)-fed mice. Accordingly, adipocyte-specific CD1d knockout (CD1dADKO) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to α-galactosylceramide (α-GC)-induced iNKT cell activation. ...

Vα24-invariant natural killer T cells (NKTs) localize to tumors and have inherent antitumor properties, making them attractive chimeric antigen receptor (CAR) carriers for redirected cancer immunotherapy. However, clinical application of CAR-NKTs has been impeded, as mechanisms responsible for NKT expansion and the in vivo persistence of these cells are unknown. Here, we demonstrated that antigen-induced expansion of primary NKTs in vitro associates with the accumulation of a CD62L+ subset and exhaustion of CD62L- cells. Only CD62L+ NKTs survived and proliferated in response to secondary stimulation. When transferred to immune-deficient NSG mice, CD62L+ NKTs persisted 5 times longer than CD62L- NKTs. Moreover, CD62L+ cells transduced with a CD19-specific CAR achieved sustained tumor regression in a B cell lymphoma model. Proliferating CD62L+ cells downregulated or maintained CD62L expression when activated via T cell receptor alone or in combination with costimulatory receptors. We generated ...

Data presented in this paper provide the first example of how negative regulation of NKT cell signalling contributes to NKT cell development. In contrast to the known NKT regulators, CYLD is dispensable for NKT cell maturation. In fact, the CYLD KO mice contain a substantially higher frequency of NK1.1+ mature NKT cells. This phenotype is associated with a hyper‐activation phenotype, particularly in the immature NKT populations. However, although loss of CYLD seems to accelerate the process of NKT cell maturation, the CYLD KO mice display a severe reduction in the number of NKT cells in both the thymus and the periphery. This deficiency is due to the massive apoptosis of immature NKT cells. Thus, in contrast to its pro‐apoptotic function implicated in other cell types, particularly tumour cells (Sun, 2010), CYLD has a potent anti‐apoptotic function in immature NKT cells, which is crucial for NKT cell development.. The hyper‐activated phenotype of CYLD KO NKT cells indicated the ...

Natural killer T (NKT) cells are thought to be involved in innate responses against infection. We investigated one specific type of NKT cell, Valpha24/Vbeta11 double positive, in hepatitis C virus (HCV) infection. Lower frequencies of this population were detected in the blood of HCV PCR-positive patients than in controls. Unlike Valpha24/Vbeta11 NKT cells found in blood, those in the liver appeared to be recently activated.

TY - JOUR. T1 - Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. AU - Gold, M. C.. AU - Eid, T.. AU - Smyk-Pearson, S.. AU - Eberling, Y.. AU - Swarbrick, G. M.. AU - Langley, S. M.. AU - Streeter, P. R.. AU - Lewinsohn, D. A.. AU - Lewinsohn, D. M.. PY - 2013/1. Y1 - 2013/1. N2 - Human mucosal-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor (TCR) Vα7.2 and are restricted by the major histocompatibility complex-Ib molecule MR1. While MAIT cells share similarities with other innate T cells, the extent to which MAIT cells are innate and their capacity to adapt is unknown. We evaluated the function of Vα7.2 + T cells from the thymus, cord blood, and peripheral blood. Although antigen-inexperienced MAIT cells displayed a naïve phenotype, these had intrinsic effector capacity in response to Mycobacterium tuberculosis (Mtb)-infected cells. Vα7.2+ effector thymocytes contained signal joint TCR gene ...

If you watched Wall-E you likely laughed at the depiction of hugely obese people riding around in hover cars drinking Big Gulps - surely a science that could create the technology to generate an entire artificial world could solve how to drink Big Gulps without turning ban happy like California or New York. |!-- --|…

Natural killer T (NKT) cells, which comprise a minor population of T cells in primary and secondary lymphoid organs, possess phenotypic characteristics of both NK and T cells. NKT cells respond to various external stimuli by an early burst of cytokines, including IL-4 and IFN-. Thus, a key immunoregulatory role has been attributed to them. Autoimmune diseases, especially type I diabetes (TID), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Furthermore, several lines of evidence exist to support the notion that an NKT cell deficiency in individuals at risk of TID may be causal to TID. As a result, targeting NKT cells using immunotherapeutic agents may prove beneficial in the prevention or recurrence of TID. Indeed, our data demonstrate that stimulation of NKT cells with a specific ligand prevents the onset and recurrence of TID in non-obese diabetic (NOD) mice ...

Alpha-galactosylceramide (α-GalCer) is a glycolipid that can be loaded into MHC-class-I-related CD1d molecules by dendritic cells and has been shown to stimulate invariant natural killer T (iNKT) cells. iNKT cells have emerged as important contributors to the regulation of immune responses, T cell activation, and anti-tumor activity. Through this activation cascade, α-GalCer exerts potent anti-tumoral and immune regulatory activities. However, the limitations were found in clinical application that (1) iNKT cells failed to produce cytokines and proliferate when additional doses of α-GalCer were given by systemic route and (2) poor hydrophilicity of α-GalCer. In this project, α-GalCer was incorporated into the lipid bilayer of the liposome, while the galactose molecular was expressed on the surface of the liposome to form a targeting liposome antigen-carrier with immunemodulatory effect. Thus, α-GalCer-incorporated liposome is capable of improving the delivery of antigen to ...

Our unit studies the mechanisms of inflammation and associated tissue damage (cartilage/bone) in musculoskeletal diseases, particularly spondyloarthritis (SpA), osteoarthritis and rheumatoid arthritis using a translational research approach. Specifically gut inflammation is investigated as a driver of joint inflammation in SpA: about 50% of patients with SpA have subclinical, microscopical bowel inflammation. Mesenchymal cells are crucial effector cells in the gut-joint axis in SpA. Regulatory cells by contrast, particularly invariant natural killer T (iNKT) cells, have a marked anti-inflammatory effect. We have a longstanding interest in the biology of iNKT cells under steady state conditions and in arthritic disease. In studying how regulatory feedback mechanisms fail in arthritic disease, we have uncovered an important functional interaction between Treg cells and iNKT cells. Another common pathogenic principle for musculoskeletal disorders is mechanical strain. In a mouse model of SpA ...

Abstract Natural killer T (NKT) cells are important regulatory lymphocytes that have been shown in mouse studies, to have a crucial role in promoting immunity to tumours, bacteria ..

NK1.1neg iNKT cells are the major iNKT subset producing IL-17. Liver MNCs from wild-type mice were stained with CD1d/α-GalCer tetramers, anti-TCRβ, and NK1.1 before sorting. (A) Representative FACS profiles obtained before (left) and after (right) sorting of CD1d/α-GalCer tetramers +NK1.1neg (NK1.1neg iNKT) and CD1d/α-GalCer tetramers +NK1.1pos (NK1.1pos iNKT) liver iNKT cells. (B-F) Sorted NK1.1neg iNKT and NK1.1pos iNKT liver MNCs were stimulated with α-GalCer (B-D) or synthetic B. burgdorferi glycolipids (BbGL-II [IIc]) or GalA-GSL (GSL; E and F) plus irradiated liver MNCs from Jα18−/− mice as APCs. Sorted CD4+CD62L+ T cells from Jα18−/− mice were stimulated with α-GalCer plus irradiated liver MNCs from Jα18−/− mice as APCs (G). 3 d later, IL-17 (B, E, and G), IL-4 (C and F), and IFN-γ (D) were measured in the supernatants. No cytokine was detected in the absence of α-GalCer stimulation, in the absence of APCs or when APCs alone were stimulated with α-GalCer (not ...

The highly conserved CD1d-restricted NKT cells, identified as a bridge between innate and adaptive immune responses, exert potent immune regulatory functions by releasing a variety immunomodulatory cytokines. Up to now, the response of NKT cells has been studied extensively by multiple groups with α-GalCer that has been proven to be a unique type of adjuvant for vaccine development (7). New analogues of α-GalCer are being synthesized to search for new NKT cell agonists that may have superior properties for the treatment of autoimmune and inflammatory diseases. One of these, α-C-GalCer was found to be more potent in helping mice to defend against mouse malaria and B16 melanoma by inducing a more prolonged IL-12 and IFN-γ response (14). Moreover, α-C-GalCer was reported bind more stably to DCs than α-GalCer, and α-C-GalCer-loaded DCs induced higher levels and longer lasting IFN-γ-producing NKT cell responses and more effective adaptive protective T-cell-mediated immunity (21).. iGb3, the ...

1995-1997 G. Perlemuter, Ph.D. Mentor. Fibrates action on HCV core protein secretion.. EDITORIAL POSITION. Ad hoc reviewer for: Journal of Virology, Journal of Clinical Microbiology, Clinical and Vaccine Immunology, Antimicrobial Agents and Chemotherapy ASM.. AWARDES AND GRANTS:. 2009-2012 ANR-MIE NKTVIR Mechanisms of activation and role of invariant Natural Killer T lymphocytes during viral infections, Co- investigator ...

Also called TCRAV7S2 according to the nomenclature from Arden et al. The iValpha7.2 segment in humans is an evolutionarily conserved invariant TCRalpha chain, expressed in mucosal associated invariant T (MAIT) cells, also called mNKT. MAIT cells are abundant in human blood (1-8% of T cells vs. 0.01-1% for NKT cells), the intestinal mucosa and mesenteric lymph nodes (MLN). MAIT cells are evolutionarily conserved innate-like T cells with anti-microbial properties. They are apparently also involved in non-infectious inflammatory disorders and in autoimmune inflammatory lesions. MAIT cells were found to specifically accumulate in the lamina propria (LP) of the intestine. This suggests that these cells may, in fact, be directed to microbial antigens presented by MR1 molecules, having a role of natural killer T cells (mNKT cells) in intestinal immunology. mNKT cells are a subset of non-conventional T cells recognizing endogenous and / or exogenous glycolipid antigens when presented by the major ...

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We have shown that LEF1 played critical and nonredundant roles in iNKT cell expansion and iNKT2 effector fate differentiation. We showed that in the absence of LEF1, iNKT cell expansion at ST0 and ST1 failed to occur and that LEF1 directly regulated expression of the CD127 component of the IL-7 receptor and the transcription factor c-myc, both of which are required for this phase of expansion (Dose et al., 2009; Mycko et al., 2009; Tani-ichi et al., 2013). LEF1 was also required for the development of iNKT2 cells, which include both IL-4 only and IL-4 plus IFNγ-producing iNKT cells, and LEF1 directly regulated the expression of the iNKT2 signature transcription factor GATA3. Our findings are particularly striking given that LEF1 deficiency has only subtle effects on conventional T cells during their differentiation and in the periphery during their activation and acquisition of the memory phenotype as the result of redundancy with the related transcription factor TCF1 (Okamura et al., 1998; Yu ...

Introduction Mucosal-Associated Invariant T cells (MAIT) are recently described human T lymphocytes with possible functions in mucosal antibacterial host defence.1 MAIT express a highly conserved T cell receptor (TCR) alpha chain consisting of an invariant Vα7.2-Jα33 rearrangement.2 Recent evidence suggests a role for T lymphocytes in the pathogenesis of chronic pancreatitis (CP), but little is known about the composition of T cell subsets in this disease.3 4 Intestinal bacterial overgrowth is common in chronic pancreatitis patients.5 We hypothesised that this antigenic load may promote MAIT infiltration of the pancreas and used flow cytometry to study T lymphocytes in resected pancreatic tissue and blood of patients with chronic pancreatitis.. ...

Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT-cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4(+) T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads ...

Natural Killer T (NKT) cells are lipid-reactive CD1d-restricted T lymphocytes important in infection cancer and autoimmunity. and self lipid antigen induction for NKT cells. Intro Natural killer T (NKT) cells are XL-888 a subpopulation of unconventional T lymphocytes that communicate a restricted T cell receptor (TCR) repertoire and several molecules characteristic for NK cells (Bendelac et al. 2007 Kronenberg 2005 Following activation NKT cells respond by a rapid burst of cytokines secreting primarily interferon-γ(IFN-γ) and interleukin-4 (IL-4) therefore regulating the quality of downstream immune reactions (Bendelac et al. 2007 Consequently NKT cells play a role in various disease conditions including infections (Tupin et al. 2007 malignancy (Cui et al. 1997 Dhodapkar 2009 and autoimmunity (Shi and Vehicle Kaer 2006 such as diabetes (Hong et al. 2001 Sharif et al. 2001 and multiple sclerosis (Miyamoto et al. 2001 NKT cells identify lipid antigens primarily belonging to the group of ...

Sulfatides are innate glycosphingolipids shown to activate a subpopulation of type II NKT cells. Their activation has been reported to sometimes have antagonistic roles to those of type I NKT cells in some disease models. This has sparked a lot of interest in the synthesis of natural and unnatural sulfatides for an examination of their influence on NKT cell responses. The design, synthesis and evaluation of type II NKT cell activation of several sulfatide ligands are described in this thesis. A two-step methodology has been developed for the rapid assembly of disubstituted β-lactones. The first step is olefin cross metathesis (CM) of a-methylene-β-lactones with various alkene cross partners to furnish a-alkylidine-β-lactones. These are subsequently diastereoselectively reduced. A diverse library of β-lactones, including (±)-nocardiolactone has been prepared. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors for several serine

Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2α in T/NKT cells and found that HIF-2α knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2α knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1+ cell depletion or Fas ligand blockade. Compared with wild-type NKT cells, HIF-2α−/− NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. ...

Natural Killer (NK) cells were initially named based on their propensity for cytolytic function in the absence of any specific kind of activation. NK cells are an important part of innate immunity, defending the body against both virally infected cells and tumor cells. Natural Killer T (NKT) cells represent a special hybrid of T cell and NK cells. They express a T cell receptor complex and several NK cell markers. Unlike T cells, they mainly recognize lipid antigen presented by CD1d and not MHCs. NKT cells are capable of producing both Th1 and Th2-related cytokines. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.

Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.

Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205+ dendritic cells (DCs) and NK1.1+ invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α-galactosylceramide (α-GalCer). Here we demonstrate that the adoptive transfer of DEC-205+ bone marrow-derived DCs cocultured with α-GalCer (DEC-205+ BMDCs-c/w-α-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium ...

Dendritic cells (DC) present alphaGalactosylceramide (alphaGalCer) to invariant T cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we demonstrated that alphaGalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was IL-2 dependent and involved both NKT and DC, since mice lacking IL-2, NKT and DC lacked any enhanced response to adoptively transferred alphaGalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of alphaGalCer from the cell membrane of the donor CD8 T cells onto the alphaGalCer receptor CD1d which is present on host DC. alphaGalCer transfer was increased by prior activation of the donor CD8 T cells and required

It has been suggested that NKT cells are biased toward CD1d autoreactivity. Consistent with this, NKT cells have an activated/effector or memory phenotype, even in germ free animals (58). Also, some NKT cell hybridomas exhibit CD1d autoreactivity (59), and freshly isolated NKT cells respond to CD1d transfectants and DCs (60). In light of this possible autoreactivity, it remained to be shown whether NKT cell precursors that encounter a strong signal during development undergo negative selection, and if so, what cell type(s) can mediate the negative selection of NKT cells. In this study, we showed that the addition of an agonist glycolipid into FTOC or increasing CD1d surface expression by transgenesis resulted in a drastic reduction of NKT cells, supporting the notion that NKT cells are susceptible to negative selection. This is the first demonstration that a glycolipid can induce negative selection of a T cell population. Although our models do not directly address whether NKT cells can be ...

Natural Killer (NK) and Natural Killer T (NKT) cells are unique lymphocytes mainly involved with innate immunity. NK cells are capable of targeting tumor cells and virus-infected cells for destruction. They routinely check target cells for the expression of particular markers, which guide them toward activation or tolerance. Natural Killer T cells are a unique hybrid, sharing qualities of both T cells and Natural Killer cells. They emigrate from the thymus, displaying NK markers and harboring the potential to launch aggressive Th1 or Th2 cytokine release. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.

Human invariant NKT (iNKT) cells are a unique subset of T cells, which recognize glycolipids presented by the CD1d. Among the iNKT cells, several functionally distinct subsets have been characterized according to CD4 and/or CD8 co-receptor expression. The current study is focussed on the CD4(+) iNKT cell subset and its role in an anti-infectious response. We have examined the role of CD4(+) iNKT cells on the intracellular Brucella suis growth. Our results indicate that CD4(+) iNKT cells impair the intramacrophagic growth of Brucella. This inhibition is due to a combination of soluble and contact-dependent mechanisms: IFN-gamma is weakly involved while cytotoxic activities such as the induction of the Fas pathway and the release of lytic granules are major mechanisms. The impairment of Brucella growth by CD4(+) iNKT cells requires an interaction with CD1d on macrophage surface. Also, we have shown that although CD4 regulates several biological responses of CD4(+) iNKT cells, it is not involved in ...

The method to generate highly antigen specific iPSC-derived killer T cells is established by Dr. Shin Kaneko, an associate professor and a leading scientist of immunotherapy using iPSC-derived killer T cells, in Center for iPS cell Research and Application, Kyoto University. The iPSC technology allows Thyas to stably supply a large quantity of tumor-specific or virus-specific T cells that have high proliferative capacity and potent killing activity. As of today, no other method produces highly antigen specific iPSC-derived killer T cells.. Novel immunotherapies have demonstrated significant benefits to cancer patients, however, the use of those is limited due to severe adverse events and therapy resistance. Thyas iPS-derived T cell products are expected to be safe and highly effective to many patients with cancers and infectious diseases. Therefore, the approach has a great clinical advantage.. About Thyas ...

It is well established that different populations of alphabeta T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules, but also foreign and self-lipids in association with CD1 proteins, which share structural similarities with MHC class I molecules. CD1 molecules are comprised of five isoforms, known as group 1 (CD1a, b, c, e) and group 2 (CD1d) CD1, presenting lipid antigens to conventional T lymphocytes or innate-like T cells bearing an invariant T cell receptor (TCR) and known as invariant NKT (iNKT) cells. During the last couple of years, several papers have been published describing important aspects of the mechanisms controlling the processing and presentation of endogenous and exogenous CD1 lipid antigens, which will be the main focus of this review.

The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional T cells known as mucosal-associated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAIT cells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ T cells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial

Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation. Proceedings of the National Academy of Sciences of the United States of America. 113. 2016 ...

Natural killer (NK) cells are derived from pluripotent hematopoietic stem cell precursors, but develop independently of the thymus. They comprise a key lymphocyte subset (approximately 10%-15% of peripheral blood mononuclear cells) and are a constituent of the innate immune system, since these cells do not rearrange their germline DNA to obtain specificity. NK cells serve an important role in host defense against viral infections, as well as tumor surveillance. They are also a component of the adaptive immune response through cytokine production. NK cell functions are governed by a balance between activating receptors and inhibitory receptors.. NK cells are identified by expression of different cell-surface receptors and they are not a homogeneous population.(1) In general, the most common combination of surface markers used to identify the majority of NK cells is the absence of CD3 (CD3-), along with expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity IgG Fc receptor-Fc ...

Natural killer (NK) cells are derived from pluripotent hematopoietic stem cell precursors, but develop independently of the thymus. They comprise a key lymphocyte subset (approximately 10%-15% of peripheral blood mononuclear cells) and are a constituent of the innate immune system, since these cells do not rearrange their germline DNA to obtain specificity. NK cells serve an important role in host defense against viral infections, as well as tumor surveillance. They are also a component of the adaptive immune response through cytokine production. NK cell functions are governed by a balance between activating receptors and inhibitory receptors.. NK cells are identified by expression of different cell-surface receptors and they are not a homogeneous population.(1) In general, the most common combination of surface markers used to identify the majority of NK cells is the absence of CD3 (CD3-), along with expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity IgG Fc ...

Definition noun A type of T cell that does not express markers of either T orB-cell lineage, but may possess fc receptors for immunoglobulin g. It functions by killing target cell through antibody-dependent cell-mediated cytotoxicity or through perforin formation, killing cells without prior sensitization (hence, the name). ...

NKT cells induce cell death in cancer cells in the similar mechanism with NK cells, but their direct cytotoxic activity is limited because they are only found in small quantities in the body. However, NKT cells do have the ability to produce large amounts of cytokine (IFN-γ, etc.). NKT cells contribute to the activate NK cells and other cells representing innate immune system and cytotoxic T cells(cytotoxic T lymphocyte: CTL) representing acquired immune system through production of IFN-γ and other helper T (Th) 1 cytokines; stimulate antibody production from B cell and induction of allergic inflammation through production of IL-4 and other Th2 cytokines; and inhibit non-allergic diseases through IL-17 production. As around 90% of NKT cells work to prevent infections, and due to the ability of NKT cells to immediately produce large amounts of cytokine upon antigen recognition without the need for clonal growth, NKT cells are currently considered to play the role of an adjuvant that activates ...

When our immune system is deficient in natural killer T-cells the body can be subjected to a variety of autoimmune disorders. Cancer and tumour growth are also related to a lack of natural killer T-cells. And without enough natural killer T-cells, a minor infection can turn into a disaster. ...

Lymphocytes expressing a Testosterone levels cell receptor (TCR) composed of Vgamma9 and Vdelta2 stores represent a small small percentage of human being thymocytes. people overlap intensive in their moving repertoire. This type of selection indicates the existence of a monomorphic antigen-presenting molecule that is definitely an subject of current study but continues to be incompletely described. While selection on a monomorphic delivering molecule may appear uncommon, related systems form the alpha dog beta Capital t cell repertoire including the intense good examples of NKT or mucosal-associated invariant Capital t cells (MAIT) and the much less dramatic amplification of general public Vbeta string rearrangements powered by specific MHC substances and connected with level of resistance to virus-like pathogens. Choosing and amplifying general public Capital t cell receptors whether alpha dog beta or gamma delta, are essential methods in developing an anticipatory TCR repertoire. Cell ...

Many types of innate (natural killer cells, natural killer T cells, and Kupffer cells/macrophages) and adaptive (T cells and B cells) immune cells are enriched ...

T cells consist of two major groups: CD4-positive T helper cells (who help other immune cells in mounting an effective response) and CD8-positive killer T cells. HIV infects and destroys CD4-positive cells, leaving patients with a crippled immune system. Throughout the course of HIV disease, however, patients have high levels of HIV-specific killer T cells. Early after initial infection, these cells are able to effectively kill the virus and reduce viral load. On the other hand, during the later stage of disease killer T cells, while still present, seem no longer able to control the virus. In an article in the November 4 issue of the Journal of Clinical Investigation, Premlata Shankar and colleagues from the Center for Blood Research at Harvard Medical School suggest why this might be the case ...

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By combining two treatment strategies, both aimed at boosting the immune systems killer T cells, Johns Hopkins researchers report they lengthened the lives of mice with skin cancer more than by using either strategy on its own. And, they say, because the combination technique is easily tailored to different types of cancer, their findings - if confirmed in humans - have the potential to enhance treatment options for a wide variety of cancer patients.

Natural killer (NK) cell consitutes white blood cells which specifically functions in lysing tumor and virus invected cells. In this research, a commercial

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