MHC-Restricted and -Unrestricted Cd8 T Cells

Rau, Laura; Cohen, Nicholas; Robert, Jacques

doi:10.1097/00007890-200112150-00020

Cited by 30 publications

(36 citation statements)

References 34 publications

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“…Phenotypic and functional characterization of anti-minor H-Ag splenic CTLs generated by priming either with skin graft or s.c. gp96 immunization is consistent with this view (25,26,32). In addition, we have shown previously that skin graft rejection requires CD8 T cells in vivo (39) and that the kinetics of CD8 T cell infiltration correlate with the onset of rejection (30).…”

Section: Discussionsupporting

confidence: 84%

Phylogenetic Conservation of Glycoprotein 96 Ability to Interact with CD91 and Facilitate Antigen Cross-Presentation

Robert

Ramanayake

Maniero

et al. 2008

The Journal of Immunology

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Although the ability of gp96 to activate APCs and generate CD8 CTLs against peptides they chaperone through interaction with the endocytic receptors CD91 is supported by solid evidence, its biological relevance in immune surveillance is debated. We have used an evolutionary approach to determine whether gp96 interacts with receptors expressed on APCs and promotes MHC class I cross-presentation of minor histocompatibility Ags (H-Ags) to CTLs in the frog Xenopus. We show that in Xenopus gp96 binds the CD91 homolog at the surface of peritoneal leukocytes, and that this binding is inhibited by molar excess of unlabeled gp96 or the CD91 ligand α2-macroglobulin, by anti-CD91 Ab and by the specific CD91 antagonist receptor-associated protein. Surface binding followed by internalization of gp96 was confirmed by fluorescent microscopy. Furthermore, adoptive transfer of peritoneal leukocytes pulsed with as little as 800 ng of gp96 chaperoning minor H-Ags, but not minor H-Ag-free gp96, induces potent CD8 T cell infiltration and Ag-specific accelerated rejection of minor H-locus disparate skin grafts. Inhibition of gp96-CD91 interaction by pretreatment with anti-CD91 Ab and receptor-associated protein impairs both CD8 T cell infiltration and acute skin graft rejection. These data provide evidence of the conserved ability of gp96 to facilitate cross-presentation of chaperoned Ags by interacting with CD91. The persistence of this biological process for >350 million years that separate mammals and amphibians from a common ancestor strongly supports the proposition that gp96 and CD91 are critically involved in immune surveillance.

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Section: Discussionsupporting

confidence: 84%

Phylogenetic Conservation of Glycoprotein 96 Ability to Interact with CD91 and Facilitate Antigen Cross-Presentation

Robert

Ramanayake

Maniero

et al. 2008

The Journal of Immunology

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“…In vivo tumorigenicity of b2m-and XNC-silenced 15/0 tumors CD8 + T cell depletion experiments have shown that even in absence of immunization, CD8 + T cells are critical in the resistance of Xenopus to the growth of transplanted 15/0 tumor [30]. We were therefore interested in determining to what extent the anti-15/0 tumor CD8 + T cell response in naive Xenopus is due to CCU-CTL effectors recognizing class Ib molecules.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were incubated with anti-CD8 mAb (IgM isotype) for 30 min on ice, and antibody-coated cells were positively selected using MACS microbeads (Miltenyi Biotec, Auburn, CA) coupled to mousespecific anti-l following the manufacturer's instructions. NKlike cells were either enriched by removing CD8 + T cells or positively selected with the anti-NK 1F8 mAb [30]. Targets were labeled for 2 h at 26 C with 5 lCi/mL [ 3 H]-thymidine (2 day-old LG-15 normal splenic PHA-induced lymphoblast targets were labeled for 20 h), washed, incubated for 4 h at different effector-to-target (E:T) ratios and harvested using a 96-well harvester (BetaplateWallac); thymidine uptake was determined by scintillation spectrometry.…”

Section: In Vitro Killing Assaymentioning

confidence: 99%

Involvement of nonclassical MHC class Ib molecules in heat shock protein‐mediated anti‐tumor responses

et al. 2007

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Nonclassical MHC class Ib (class Ib) genes are found in all jawed vertebrates, and their products are hypothesized to be indicators of intracellular stress and malignancy. They may be involved in immune recognition of classical MHC class Ia (class Ia)‐low or ‐negative tumor cells through their interaction with T cell receptors and/or non‐T cell inhibitory or triggering receptors expressed by NK cells and T cells. In the frog Xenopus, the molecular chaperone gp96 mediates a potent immune response involving antigen‐specific classical class Ia‐unrestricted CD8+ CTL (CCU‐CTL) against a transplantable thymic tumor (15/0) that does not express class Ia molecules. We hypothesized that Xenopus nonclassical class Ib gene products (XNC) are involved in gp96‐mediated CCU‐CTL anti‐tumor responses. To investigate the involvement of class Ib gene products in Xenopus anti‐tumor responses, we generated, for the first time in ectothermic vertebrates, stable tumor transfectants expressing short hairpin RNA (shRNA) to silence either XNC directly or β2m to prevent class Ib surface expression. Both types of 15/0 transfectants are more resistant to CCU‐CTL killing, more tumorigenic and more susceptible to NK‐like cell killing. This study provides in vitro and in vivo evidence of the evolutionary conservation of class Ib involvement in anti‐tumor CD8+ T cell responses.

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“…Griffiths et al (42) reported that Qa-1 molecules, the murine homologues of human HLA-E that bind leader peptides of class I H chains and promote allogeneic antitumor responses, may also contribute to the rejection of melanoma cells in syngeneic hosts. In the African clawed frog, Xenopus laevis, CD8 ϩ T cells were shown to reject syngeneic class Ia-negative tumor (43). Because the frog tumor cells express class Ib transcripts (44), it was proposed that the antitumor cytotoxic response operates via class Ib Ags.…”

Section: Cd8mentioning

confidence: 99%

A Nonclassical MHC Class I Molecule Restricts CTL-Mediated Rejection of a Syngeneic Melanoma Tumor

Chiang

Stroynowski

2004

The Journal of Immunology

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Although CTL and polymorphic, classical MHC class I molecules have well defined roles in the immune response against tumors, little is currently known regarding the participation of nonpolymorphic, nonclassical MHC class I in antitumor immunity. Using an MHC class I-deficient melanoma as a model tumor, we demonstrate that Q9, a murine MHC class Ib molecule from the Qa-2 family, expressed on the surface of tumor cells, protects syngeneic hosts from melanoma outgrowth. Q9-mediated protective immunity is lost or greatly diminished in mice deficient in CTL, including β2-microglobulin knockout (KO), CD8 KO, and SCID mice. In contrast, the Q9 antitumor effects are not detectably suppressed in CD4 KO mice with decreased Th cell activity. Killing by antitumor CTL in vitro is Q9 specific and can be blocked by anti-Q9 and anti-CD8 Abs. The adaptive Q9-restricted CTL response leads to immunological memory, because mice that resist the initial tumor challenge reject subsequent challenges with less immunogenic tumor variants and show expansion of CD8+ T cell populations with an activated/memory CD44high phenotype. Collectively, these studies demonstrate that a MHC class Ib molecule can serve as a restriction element for antitumor CTL and mediate protective immune responses in a syngeneic setting.

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MHC-Restricted and -Unrestricted Cd8 T Cells

Abstract: For the first time, CD8 T cells have been shown to be involved in acute skin allograft rejection in an ectothermic vertebrate. Our data also suggest that, at least in Xenopus, T cells that express a CD8 epitope may be effectors in MHC-unrestricted anti-tumor responses.

Cited by 30 publications

References 34 publications

Phylogenetic Conservation of Glycoprotein 96 Ability to Interact with CD91 and Facilitate Antigen Cross-Presentation

Phylogenetic Conservation of Glycoprotein 96 Ability to Interact with CD91 and Facilitate Antigen Cross-Presentation

Involvement of nonclassical MHC class Ib molecules in heat shock protein‐mediated anti‐tumor responses

A Nonclassical MHC Class I Molecule Restricts CTL-Mediated Rejection of a Syngeneic Melanoma Tumor

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