Journal
CELL REPORTS
Volume 14, Issue 5, Pages 1232-1245Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.099
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Funding
- British Heart Foundation
- National Institute of Health Research Cambridge Biomedical Research Centre
- National Institute of Health Research Blood and Transplant Research Unit
- Wellcome Trust
- Raymond Scholarship
- Academy of Medical Sciences/Wellcome Trust starter grant
- Beverly Sackler Scholarship
- British Heart Foundation [FS/10/018/28193, FS/12/87/29899] Funding Source: researchfish
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MHC alloantigen is recognized by two pathways: directly,'' intact on donor cells, or indirectly,'' as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.
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