scholarly journals Induction of M3-Restricted Cytotoxic T Lymphocyte Responses by N-Formylated Peptides Derived from Mycobacterium tuberculosis

2001 ◽  
Vol 193 (10) ◽  
pp. 1213-1220 ◽  
Author(s):  
Taehoon Chun ◽  
Natalya V. Serbina ◽  
Dawn Nolt ◽  
Bin Wang ◽  
Nancy M. Chiu ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Spleen And Lymph Nodes ◽  
Mhc Class Ia ◽  
Lymphocyte Responses ◽  
Peptide Binding Assay ◽  
Class Ib

Major histocompatibility complex (MHC) class I–restricted CD8+ T cells play a critical role in the protective immunity against Mycobacterium tuberculosis (Mtb). However, only a few Mtb peptides recognized by MHC class Ia–restricted CD8+ T cells have been identified. Information on epitopes recognized by class Ib–restricted T cells is even more limited. M3 is an MHC class Ib molecule that preferentially presents N-formylated peptides to CD8+ T cells. Because bacteria initiate protein synthesis with N-formyl methionine, the unique binding specificity of M3 makes it especially suitable for presenting these particular bacterial epitopes. We have scanned the full sequence of the Mtb genome for NH2-terminal peptides that share features with other M3-binding peptides. Synthetic peptides corresponding to these sequences were tested for their ability to bind to M3 in an immunofluorescence-based peptide-binding assay. Four of the N-formylated Mtb peptides were able to elicit cytotoxic T lymphocytes (CTLs) from mice immunized with peptide-coated splenocytes. The Mtb peptide–specific, M3-restricted CTLs lysed the Mtb-infected macrophages effectively, suggesting that these N-formylated Mtb peptides are presented as the naturally processed epitopes by Mtb-infected cells. Furthermore, T cells from Mtb-infected lungs, spleen, and lymph nodes responded to N-formylated Mtb peptides in an M3-restricted manner. Taken together, our data suggest that M3-restricted T cells may participate in the immune response to Mtb.

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

2006 ◽  
Vol 203 (2) ◽  
pp. 449-459 ◽  
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.

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

2008 ◽  
Vol 205 (7) ◽  
pp. 1647-1657 ◽  
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.

scholarly journals Susceptibility of Mice Deficient in CD1D or TAP1 to Infection with Mycobacterium tuberculosis

1999 ◽  
Vol 189 (12) ◽  
pp. 1973-1980 ◽  
Author(s):  
Samuel M. Behar ◽  
Chris C. Dascher ◽  
Michael J. Grusby ◽  
Chyung-Ru Wang ◽  
Michael B. Brenner
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Critical Role ◽  
Cell Subset ◽  
Interferon Γ ◽  
Class I ◽  
Class I Mhc ◽  
Deficient Mice

Cellular immunity against Mycobacterium tuberculosis controls infection in the majority of infected humans. Studies in mice have delineated an important role for CD4+ T cells and cytokines including interferon γ and tumor necrosis factor α in the response to infection with mycobacteria. Recently, the identification of CD8+ CD1-restricted T cells that kill M. tuberculosis organisms via granulysin and the rapid death after infection of β2 microglobulin deficient mice in humans has drawn attention to a critical role for CD8+ T cells. The nature of mycobacterial-specific CD8+ T cells has been an enigma because few have been identified in any species. Here, we delineate the contribution of class I MHC–restricted T cells in the defense against tuberculosis as transporter associated with antigen processing (TAP)1-deficient mice died rapidly, bore a greater bacterial burden, and had more severe tissue pathology than control mice. In contrast, CD1D−/− mice were not significantly different in their susceptibility to infection than control mice. This data demonstrates a critical role for TAP-dependent peptide antigen presentation and provides further evidence that class I MHC–restricted CD8+ T cells, the major T cell subset activated by this antigen processing pathway, play an essential role in immunity to tuberculosis.

scholarly journals Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

2020 ◽  
Vol 117 (11) ◽  
pp. 6042-6046 ◽  
Author(s):  
John Y. Choi ◽  
Siawosh K. Eskandari ◽  
Songjie Cai ◽  
Ina Sulkaj ◽  
Jean Pierre Assaker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Antibody Responses ◽  
Heart Graft ◽  
Transplanted Organs ◽  
Class Ib

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)–CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1–restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

scholarly journals MHC Class Ia Empowers MHC Class Ib-restricted CD8+ T Cells with Strong Tumoricidal Capacity

2021 ◽  
Author(s):  
Yufang Shi ◽  
Qing Li ◽  
Liangyu Lin ◽  
Peishun Shou ◽  
Liu Keli ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Priming Effect ◽  
Mhc Class Ib ◽  
Wild Type ◽  
Mhc Haplotype ◽  
Mhc Class Ia ◽  
Class Ib

Abstract The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy.

scholarly journals Peptide Immunization Elicits Polyomavirus-Specific MHC Class Ib-Restricted CD8 T Cells in MHC Class Ia Allogeneic Mice

2013 ◽  
Vol 26 (1) ◽  
pp. 109-113 ◽  
Author(s):  
Amelia R. Hofstetter ◽  
Brian D. Evavold ◽  
Aron E. Lukacher
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Mhc Class Ib ◽  
Mhc Class Ia ◽  
Class Ib

scholarly journals EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii89-ii89
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting ◽  
Spleen And Lymph Nodes ◽  
Mouse Glioma

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

scholarly journals Human CD8+ T-cells Recognizing Peptides from Mycobacterium tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

2015 ◽  
Vol 11 (3) ◽  
pp. e1004671 ◽  
Author(s):  
Krista E. van Meijgaarden ◽  
Mariëlle C. Haks ◽  
Nadia Caccamo ◽  
Francesco Dieli ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
T Cell Subset ◽  
Human T Cell

scholarly journals Impaired Degranulation and Proliferative Capacity of Mycobacterium tuberculosis–Specific CD8+ T Cells in HIV-Infected Individuals With Latent Tuberculosis

2014 ◽  
Vol 211 (4) ◽  
pp. 635-640 ◽  
Author(s):  
Ameeta S. Kalokhe ◽  
Toidi Adekambi ◽  
Chris C. Ibegbu ◽  
Susan M. Ray ◽  
Cheryl L. Day ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd8 T Cells ◽  
Latent Tuberculosis ◽  
Proliferative Capacity

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

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