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Cross-primed CD8+ T cells mediate graft rejection via a distinct effector pathway

Abstract

To prevent bystander destruction of healthy host tissues, cytotoxic CD8+ T lymphocytes are fitted with specific receptors that direct their destructive forces specifically against chosen targets. We show here, however, that anti–H-Y monospecific, H-2b–restricted MataHari CD8+ T cells reject H-2k male skin grafts, with which they cannot directly interact. Such rejection is interferon-γ–dependent and only occurs if the recipient endothelium expresses H-2b. The findings suggest an alternate indirect effector pathway that requires processing and presentation of the donor H-Y antigen by recipient endothelium and have implications for both transplantation and autoimmune disease.

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Figure 1: Phenotypic and functional characterization of CD8+ T cells in MataHari RAG-1−/− mice.
Figure 2: CD8+ T cells are primed to both directly and indirectly presented peptide epitopes after H-Y–disparate skin graft rejection.
Figure 3: Female MataHari mice reject C3H male but not female skin, despite a lack of direct recognition.
Figure 4: The indirect effector function of CD8+ T cells is dependent on IFN-γ but not Fas-FasL.
Figure 5: Histology of heterotopic cardiac allografts transplanted into female MataHari recipients.
Figure 6: Aortic endothelial cells can present male antigen to MataHari T cells.

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Acknowledgements

Funded by National Institutes of Health grant AI-43578-01 (to P. S. H.); grants from the Etablissement Français des greffes, Association de la recherche sur le cancer and the French ministry of Research (to O. L.); and the National Kidney Foundation (P. S. H.). We thank X. Sastre for analyzing the skin graft histology; Y. Demir for help with immunohistochemical staining; and E. Skornicka for help with isolation of the endothelial cells.

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Correspondence to Peter S. Heeger.

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Supplementary information

Web Fig. 1.

Skin graft histology. H&E-stained B6 male (a,b) or C3H male (c-e) skin grafts obtained on day 7-15 after placement on female MataHari recipients. Note that the B6 grafts are extensively infiltrated with mononuclear cells and there is evidence of epidermal necrosis. The C3H grafts are characterized by marked fibrosis with little necrosis. The photographs are fully representative of 5 individual male C3H grafts and 3 individual male B6 grafts studied. Magnification: a-d: 40×; e: 100×. Histologic characteristics of isografts and C3H female grafts were no different from native skin and revealed no evidence of infiltration or fibrosis (data not shown). (PDF 305 kb)

Web Fig. 2.

Placement of C3H male heart grafts cross primes MataHari T cells in vivo. (a) Flow cytometry histogram using spleen cells obtained from a naive MataHari female (top) or a MataHari female 70 days after placement of an H-2k male heart transplant (bottom) after gating on Vβ8.3+ T cells. (solid line) anti-CD44, (dashed line) isotype control. The results are representative of 3 individual animals studied per group. (b) IFN-γ ELISPOT assays using spleen cells from naïve MataHari females or MataHari females 70 days after transplantation with a C3H male heart graft mice restimulated with H-Ypb. Each line represents the results of an individual animal. Each point is the mean value of duplicate wells as counted by our computer assisted image analyzer (<10% variability between wells). (PDF 37 kb)

Web Fig. 3.

Histology of skin grafts in RAG-1-/-γc-/- recipient mice. H&E-stained sections of skin grafts obtained 6 weeks after transplantation. H-2k male skin was placed either onto H-2k RAG-1-/-γc-/- female recipients (a) or H-2b RAG-1-/-γc-/- female recipients (b,c) adoptively transferred with female MataHari spleen cells. Note the lack of hair follicles and sebaceous glands (b) and focal mononuclear cell infiltrates c. The photographs are fully representative of the histologic findings for 3-6 animals per group. (PDF 191 kb)

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Valujskikh, A., Lantz, O., Celli, S. et al. Cross-primed CD8+ T cells mediate graft rejection via a distinct effector pathway. Nat Immunol 3, 844–851 (2002). https://doi.org/10.1038/ni831

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