scholarly journals Characterization of Human CD8+ T Cells Reactive with Mycobacterium tuberculosis–infected Antigen-presenting Cells

1998 ◽  
Vol 187 (10) ◽  
pp. 1633-1640 ◽  
Author(s):  
David M. Lewinsohn ◽  
Mark R. Alderson ◽  
Andria L. Briden ◽  
Stanley R. Riddell ◽  
Steven G. Reed ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Class I ◽  
Target Cells ◽  
Human Immune Response ◽  
Infected Cells ◽  
Antigen Presenting

Previous studies in murine models, including those using the β2 microglobulin knockout mouse, have suggested an important role for CD8+ T cells in host defense to Mycobacterium tuberculosis (Mtb). At present, little is understood about these cells in the human immune response to tuberculosis. This report demonstrates the existence of human Mtb-reactive CD8+ T cells. These cells are present preferentially in persons infected with Mtb and produce interferon γ in response to stimulation with Mtb-infected target cells. Recognition of Mtb-infected cells by these CD8+ T cells is restricted neither by the major histocompatibility complex (MHC) class I A, B, or C alleles nor by CD1, although it is inhibited by anti–MHC class I antibody. The Mtb-specific CD8+ T cells recognize an antigen which is generated in the proteasome, but which does not require transport through the Golgi-ER. The data suggest the possible use of nonpolymorphic MHC class Ib antigen presenting structures other than CD1.

scholarly journals Host ER–parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii–infected dendritic cells

2009 ◽  
Vol 206 (2) ◽  
pp. 399-410 ◽  
Author(s):  
Romina S. Goldszmid ◽  
Isabelle Coppens ◽  
Avital Lev ◽  
Pat Caspar ◽  
Ira Mellman ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Toxoplasma Gondii ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Parasitophorous Vacuole ◽  
Host Cells ◽  
Class I ◽  
Cross Presentation ◽  
Infected Cells

Toxoplasma gondii tachyzoites infect host cells by an active invasion process leading to the formation of a specialized compartment, the parasitophorous vacuole (PV). PVs resist fusion with host cell endosomes and lysosomes and are thus distinct from phagosomes. Because the parasite remains sequestered within the PV, it is unclear how T. gondii–derived antigens (Ag’s) access the major histocompatibility complex (MHC) class I pathway for presentation to CD8+ T cells. We demonstrate that recruitment of host endoplasmic reticulum (hER) to the PV in T. gondii–infected dendritic cells (DCs) directly correlates with cross-priming of CD8+ T cells. Furthermore, we document by immunoelectron microscopy the transfer of hER components into the PV, a process indicative of direct fusion between the two compartments. In strong contrast, no association between hER and phagosomes or Ag presentation activity was observed in DCs containing phagocytosed live or dead parasites. Importantly, cross-presentation of parasite-derived Ag in actively infected cells was blocked when hER retrotranslocation was inhibited, indicating that the hER serves as a conduit for the transport of Ag between the PV and host cytosol. Collectively, these findings demonstrate that pathogen-driven hER–PV interaction can serve as an important mechanism for Ag entry into the MHC class I pathway and CD8+ T cell cross-priming.

Nitrosylation of Platelet MHC Class I Molecules Directs Their Movement into the Immunosuppressive MHC Class I Processing Pathway within Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 837-837
Author(s):  
John W. Semple ◽  
Edwin R. Speck ◽  
John Freedman
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Brefeldin A ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Antigen Presenting ◽  
Platelet Transfusions

Abstract Previous studies have demonstrated that recipient mice require the production of nitric oxide (NO) within their antigen presenting cells (APC) in order to generate IgG anti-donor immunity against allogeneic platelet transfusions. NO has a complex biochemistry and several of its conjurors could be involved in this response; the most obvious is peroxynitrite (ONOO-) generated by the spontaneous combination of NO and superoxide (O2•−). ONOO- is a potent oxidant that can spontaneously nitrosylate lysine and tyrosine residues in proteins within the phagolysosome. To address the role of ONOO- in platelet immunity, we transfused GP91 PHOX knockout mice that lack the ability to produce O2•− and thus ONOO-. Results show that when wild type C57BL/6 mice were transfused with allogeneic BALB/c platelets, they developed a weak IgG anti-donor antibody response by the fifth transfusion. In contrast, PHOX KO mice generated IgG anti-donor antibodies by the 2nd transfusion and their IgG anti-donor antibody titres were significantly higher than the WT recipients. This suggested that ONOO- and protein nitrosylation may be linked with an immunosuppressive event within the recipient. This was confirmed by demonstrating that in vitro nitrosylation of platelet antigens with the ONOO- donor SIN-1 inhibited the ability of the platelets to mount an IgG immune response when transfused into allogeneic recipients. Nitrosylated platelet antigen trafficking within recipient APC was assessed by using adherent macrophages and various inhibitors of processing. When adherent APC were pulsed with nitrosylated platelet antigens in the presence of either Brefeldin A or proteosome inhibitors, IgG anti-platelet immunity against the platelets was restored. Furthermore, the IgG immunity could also be rescued against the nitrsosylated platelets if the recipients were first depleted of CD8+ T cells by injection of a monoclonal antibody. These results suggest that if platelet antigens are nitrosylated within antigen presenting cells, they are preferentially shunted to the MHC class I processing pathway and presented to CD8+ T cells that suppress the IgG immune response. Thus, it appears that reactive oxygen species act as intracellular regulators that determine whether a productive IgG immune response against platelet transfusions will occur.

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.

Reactivity and Specificity of CD8+ T Cells in Mice with Defects in the MHC Class I Antigen-Presenting Pathway

1996 ◽  
Vol 151 (1) ◽  
pp. 123-148 ◽  
Author(s):  
Hans-Gustaf Ljunggren ◽  
Richard Glas ◽  
Johan K. Sandberg ◽  
Klas Karre
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Mhc Class I Antigen ◽  
Antigen Presenting

Vagaries of the ELISpot assay: Specific detection of antigen responsive cells requires purified CD8+ T cells and MHC class I expressing antigen presenting cell lines

2015 ◽  
Vol 157 (2) ◽  
pp. 216-225 ◽  
Author(s):  
Yannick F. Fuchs ◽  
Gregor W. Jainta ◽  
Denise Kühn ◽  
Carmen Wilhelm ◽  
Marc Weigelt ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Elispot Assay ◽  
Class I ◽  
Specific Detection ◽  
Antigen Presenting Cell ◽  
Antigen Presenting

scholarly journals Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3300-3307 ◽  
Author(s):  
Paul R. Hess ◽  
Carie Barnes ◽  
Matthew D. Woolard ◽  
Michael D. L. Johnson ◽  
John M. Cullen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Therapeutic Potential ◽  
Class I ◽  
Target Cells ◽  
Type I ◽  
Ribosome Inactivating Protein ◽  
Cell Immunity

Abstract CD8+ cytotoxic T lymphocytes (CTLs) are important effector cells responsible for tissue destruction in several autoimmune and allograft-related diseases. To discover if pathogenic T cells could be selectively deleted, we investigated the ability of a toxin coupled to major histocompatibility complex (MHC) class I tetramers to kill antigen-specific CD8+ T cells. H2-Db tetramers were assembled using streptavidin conjugated to the ribosome-inactivating protein (RIP) saporin (SAP). These tetramers inhibited ribosome activity in vitro, retained the T-cell receptor (TCR)–binding specificity of their nontoxic counterparts, and were internalized by 100% of target cells, leading to cell death in 72 hours. Cytotoxicity was dependent on the tetramer dose and avidity for the T cell. A single injection of the SAP-coupled tetramer eliminated more than 75% of cognate, but not control, T cells. This work demonstrates the therapeutic potential of cytotoxic tetramers to selectively eradicate pathogenic clonotypes while leaving overall T-cell immunity intact.

CD4 Cells Engineered to Express an MHC Class I Restricted TCR Can Rescue CD8 Cells Tolerized to Tumour-Associated Antigens

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 952-952
Author(s):  
Sara Ghorashian ◽  
Ben Carpenter ◽  
Angelika Holler ◽  
Emma Nicholson ◽  
Maryam Ahmadi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Target Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cognate Antigen ◽  
Cd4 Help

Abstract Abstract 952 Background: The efficacy of T cell therapies for cancer may be limited when targeting tumour-associated antigens (TAA) which are also self-antigens. Ongoing exposure to TAA on normal cells may lead to tolerance via anergy or exhaustion of antigen-specific T cells. Methods: We have designed a model of tolerance to TAA in which T cell receptor (TCR)-transduced CD8 T cells recognise pMDM2, a TAA that is also a ubiquitous self-antigen. CD8+ T cells were transduced with pMDM2-specific TCR (MDM-CD8) and transferred to sub-lethally irradiated B6 mice that express pMDM2 in the context of MHC Class I (H2-Kb). MDM-CD8 cells are detectable 4 weeks after transfer but show defective in vivo killing of target cells pulsed with MDM2 peptide. We have used this model to determine the mechanism of tolerance and to evaluate whether tolerant CD8+ T cells can be rescued by CD4 help. Results: To determine whether tolerance of MDM-CD8 cells was dependent upon recognition of cognate antigen, we transferred MDM-CD8 cells into mice of a different MHC background (BALB/c) which lack H2-Kb required for presentation of the TCR-recognised MDM2 peptide. When BALB/c MDM-CD8 cells were transferred to BALBc hosts their functions were preserved and they retained efficient antigen-specific cytolysis. To determine whether tolerance could be modified by provision of CD4+ T cell help, we co-transferred MDM-CD8 with transgenic OT-II CD4+ cells. OT-II cells were primed with dendritic cells (DCs) loaded with cognate pOVA323-339 or irrelevant peptide. When activated through their TCR, OT-II cells increased both the frequency of MDM2-specific CD8 cells and their cytotoxic functions, indicating that CD4 help can overcome CD8 tolerance to TAA. Ineffective antigen presentation to CD4 cells and lack of known MHC class II-restricted TAA are major limitations to providing CD4 help in T cell therapy for cancer. We therefore tested whether transfer of the MHC Class I-restricted MDM2 TCR into CD4 cells could provide help upon transfer to antigen-expressing hosts. Co-transfer of MDM2-TCR-transduced CD4 cells with CD8 cells improved antigen-specific killing of target cells when compared to single transfer of either TCR-transduced CD8 or CD4 cells. Conclusion: CD4 cells rendered capable of responding to an MHC class I restricted TAA by TCR transfer can rescue tolerance developing in a CD8 population with the same specificity. This is potentially a novel way to circumvent defective immune responses arising in adoptively transferred effector cells due to prolonged exposure to cognate antigen on normal host cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

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