Expression of CD1d Under the Control of a MHC Class Ia Promoter Skews the Development of NKT Cells, But Not CD8+ T Cells

Abstract NKT cells from naïve mice are mainly CD4+ or CD4−CD8−. However, it has been reported that CD8+ NKT cells can be expanded in vitro from splenocytes, bone marrow cells and thymocytes of C57BL/6 (B6) mice by stimulation with anti-CD3 mAb and cytokines, and that the expanded CD8+ NKT cells mediate strong graft-vs.-leukemic (GVL) effects without severe GVHD after adoptive transfer into allogeneic mice. We now describe the presence of CD8+NK1.1+ cells in recipient livers (approximately 2–6%), but not in other tissues (spleen, lung, bone marrow, thymus and PBMC), in various allogeneic hematopoietic cell transplantation (allo-HCT) models. The generation of CD8+NK1.1+ cells is likely a consequence of alloresponses, as these cells were not detected in the liver of syngeneic HCT controls. Flow cytometric analysis confirmed that these cells are CD1d-independent, TCRαβ+ T cells with a memory phenotype (CD44+ and CD62L−), and do not express CD49b, Ly-49C/I, Ly-49G2, or Ly-49D. In a sublethally (6 Gy)-irradiated B6-to-B6D2F1 allo-HCT model, NK1.1+ CD8 T cells became detectable by week 2, increased in number until approximately week 8, and gradually declined thereafter but were still detectable in the liver at day 100 after allo-HCT. By using CD45.1 and CD45.2 congeneic donors, we determined that the majority of NK1.1+ CD8 T cells were derived from the donor splenocytes. Furthermore, depletion of CD8+, but not NK1.1+, cells from the donor splenocytes prior to transplantation prevented the generation of NK1.1+ CD8 T cells, indicating that these cells were derived from donor NK1.1−CD8+ splenic T cells. Our data demonstrate that donor CD8 T cells can acquire NK1.1 expression upon activation in allo-HCT recipients, and that these NK1.1+ CD8 T cells maintain a memory phenotype and persist in the recipients with preferential accumulation in the liver. Studies are currently in progress to determine the role of activated donor NK1.1+ CD8 T cells in GVHD and GVL effects.

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Invariant NKT Cells Exacerbate Type 1 Diabetes Induced by CD8 T Cells

The Journal of Immunology ◽

10.4049/jimmunol.175.4.2091 ◽

2005 ◽

Vol 175 (4) ◽

pp. 2091-2101 ◽

Cited By ~ 25

Author(s):

Thibault Griseri ◽

Lucie Beaudoin ◽

Jan Novak ◽

Lennart T. Mars ◽

Françoise Lepault ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd8 T Cells ◽

Nkt Cells ◽

Invariant Nkt Cells

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Impaired response to Listeria in H2-M3–deficient mice reveals a nonredundant role of MHC class Ib–specific T cells in host defense

Journal of Experimental Medicine ◽

10.1084/jem.20051866 ◽

2006 ◽

Vol 203 (2) ◽

pp. 449-459 ◽

Cited By ~ 38

Author(s):

Honglin Xu ◽

Taehoon Chun ◽

Hak-Jong Choi ◽

Bin Wang ◽

Chyung-Ru Wang

Keyword(s):

T Cells ◽

T Cell ◽

Host Defense ◽

Cd8 T Cells ◽

Mhc Class Ib ◽

Cell Responses ◽

Mhc Class Ia ◽

Deficient Mice ◽

Class Ib

The major histocompatibility complex (MHC) class Ib molecule H2-M3 primes the rapid expansion of CD8+ T cells by presenting N-formylated bacterial peptides. However, the significance of H2-M3–restricted T cells in host defense against bacteria is unclear. We generated H2-M3–deficient mice to investigate the role of H2-M3 in immunity against Listeria monocytogenes (LM), a model intracellular bacterial pathogen. H2-M3–deficient mice are impaired in early bacterial clearance during primary infection, with diminished LM-specific CD8+ T cell responses and compromised innate immune functions. Although H2-M3–restricted CD8+ T cells constitute a significant proportion of the anti-listerial CD8+ T cell repertoire, the kinetics and magnitude of MHC class Ia–restricted T cell responses are not altered in H2-M3–deficient mice. The fact that MHC class Ia–restricted responses cannot compensate for the H2-M3–mediated immunity suggests a nonredundant role of H2-M3 in the protective immunity against LM. Thus, the early H2-M3–restricted response temporally bridges the gap between innate and adaptive immune responses, subsequently affecting the function of both branches of the immune system.

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MP46-18 CD8 T CELLS INHIBIT THE INTERLEUKIN-15 (IL-15) INDUCED CYTOTOXIC ACTIVITY OF NK AND NKT CELLS TOWARD TUMOUR CELLS IN THE PROSTATE CANCER MICROENVIRONMENT.

The Journal of Urology ◽

10.1016/j.juro.2015.02.1581 ◽

2015 ◽

Vol 193 (4S) ◽

Cited By ~ 1

Author(s):

Oussama Elhage ◽

Christina Sakellariou ◽

Richard A. Smith ◽

Christine Galustian ◽

Prokar Dasgupta

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Cytotoxic Activity ◽

Cd8 T Cells ◽

Nkt Cells ◽

Tumour Cells ◽

Cancer Microenvironment ◽

Interleukin 15

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Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.648917 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rong Tang ◽

Xiaomeng Liu ◽

Chen Liang ◽

Jie Hua ◽

Jin Xu ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Single Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Cd8 T Cells ◽

Nkt Cells ◽

Ductal Adenocarcinoma ◽

Hematopoietic Stem ◽

Single Cell Sequencing ◽

Prognostic Implications

Background: The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment.Methods: A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature.Results: A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of “targets” for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits.Conclusion: This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.

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NKT cells and CD8+ T cells are dispensable for T cell dependent allergic airway inflammation

Protocol Exchange ◽

10.1038/nprot.2007.32 ◽

2007 ◽

Author(s):

Jyoti Das ◽

Paul Eynott ◽

Luc Van Kaer ◽

Yufang Shi ◽

Gobardhan Das

Keyword(s):

T Cells ◽

T Cell ◽

Airway Inflammation ◽

Cd8 T Cells ◽

Allergic Airway Inflammation ◽

Nkt Cells

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Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection

The Journal of Immunology ◽

10.4049/jimmunol.2100334 ◽

2021 ◽

pp. ji2100334

Author(s):

Jason M. Zimmerer ◽

Bryce A. Ringwald ◽

Sachi R. Chaudhari ◽

Jing Han ◽

Chelsea M. Peterson ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Allograft Rejection ◽

Nkt Cells ◽

Invariant Nkt Cells

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An MHC class Ib–restricted CD8 T cell response confers antiviral immunity

Journal of Experimental Medicine ◽

10.1084/jem.20080570 ◽

2008 ◽

Vol 205 (7) ◽

pp. 1647-1657 ◽

Cited By ~ 26

Author(s):

Phillip A. Swanson ◽

Christopher D. Pack ◽

Annette Hadley ◽

Chyung-Ru Wang ◽

Iwona Stroynowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Mhc Class Ib ◽

Wild Type ◽

Mhc Class Ia ◽

Class Ib

Although immunity against intracellular pathogens is primarily provided by CD8 T lymphocytes that recognize pathogen-derived peptides presented by major histocompatibility complex (MHC) class Ia molecules, MHC class Ib–restricted CD8 T cells have been implicated in antiviral immunity. Using mouse polyoma virus (PyV), we found that MHC class Ia–deficient (Kb−/−Db−/−) mice efficiently control this persistently infecting mouse pathogen. CD8 T cell depletion mitigates clearance of PyV in Kb−/−Db−/− mice. We identified the ligand for PyV-specific CD8 T cells in Kb−/−Db−/− mice as a nonamer peptide from the VP2 capsid protein presented by Q9, a member of the β2 microglobulin–associated Qa-2 family. Using Q9-VP2 tetramers, we monitored delayed but progressive expansion of these antigen-specific CD8αβ T cells in Kb−/−Db−/− mice. Importantly, we demonstrate that Q9-VP2–specific CD8 T cells more effectively clear wild-type PyV than a VP2 epitopenull mutant PyV. Finally, we show that wild-type mice also generate Q9-restricted VP2 epitope–specific CD8 T cells to PyV infection. To our knowledge, this is the first evidence for a defined MHC class Ib–restricted antiviral CD8 T cell response that contributes to host defense. This study motivates efforts to uncover MHC class Ib–restricted CD8 T cell responses in other viral infections, and given the limited polymorphism of MHC class Ib molecules, it raises the possibility of developing peptide-based viral vaccines having broad coverage across MHC haplotypes.

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