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Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: An alternative mechanism of allorecognition

Abstract

Despite evidence that human non-hematopoietic cells, such as vascular endothelium, can activate allogeneic T lymphocytes in vitro, the prevailing view has been that hematopoietic antigen-presenting cells are required to trigger alloimmune responses in vivo. Here we report that mouse non-hematopoietic cells activate alloreactive CD8+ T lymphocytes in vitro and in vivo. We also show that vascularized cardiac allografts are acutely rejected via CD8+ direct allorecognition even if the alloantigen is not presented by hematopoietic professional antigen-presenting cells. Because activation of alloreactive CD8+ T cells by donor-type non-hematopoietic cells can continue for the life of the allograft, these findings present a new clinically relevant mechanism of allorecognition and should be taken into consideration when developing strategies to prevent allograft vasculopathy or to induce tolerance.

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Figure 1: In vitro proliferative responses of BM3 CD8+ T cells.
Figure 2: In vivo proliferative responses of BM3 CD8+ T cells.
Figure 3: Assessment of hematopoietic contamination of endothelial cell cultures.
Figure 4: In vitro responses of BM3 CD8+ T cells after coculture with B6 vascular endothelium.
Figure 5: Cardiac allograft survival, histology and graft-infiltrating cells in BM3 mice.
Figure 6: Cardiac allograft survival, histology and graft-infiltrating cells in CBA mice.

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Acknowledgements

We thank A. Mellor for the BM3 mice and the clonotypic antibody Ti98; H. Chen for technical assistance; and P.C. Nowell, M.I. Greene, C.H. June and J.S. Moore for critical review of the manuscript. This work was supported by grants from NIH (AI47257-01A1; AI-37691; AI-43626; AI-41521) as well as the Craig and Elaine Dobbin Research Fund.

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Correspondence to Bruce R. Rosengard.

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Kreisel, D., Krupnick, A., Gelman, A. et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: An alternative mechanism of allorecognition. Nat Med 8, 233–239 (2002). https://doi.org/10.1038/nm0302-233

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