Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It.
Ali, Jason M
Negus, Margaret C
Conlon, Thomas M
Harper, Ines G
Qureshi, M Saeed
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Ali, J. M., Negus, M. C., Conlon, T. M., Harper, I. G., Qureshi, M. S., Motallebzadeh, R., Willis, R., et al. (2016). Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It.. Cell Rep, 14 (5), 1232-1245. https://doi.org/10.1016/j.celrep.2015.12.099
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.
Adaptive Immunity, Animals, Antigen Presentation, CD4-Positive T-Lymphocytes, Heart Transplantation, Histocompatibility Antigens Class I, Immunity, Innate, Isoantigens, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, Peptides, Transplantation, Homologous
This work was supported by a British Heart Foundation project grant, the National Institute of Health Research Cambridge Biomedical Research Centre, and the National Institute of Health Research Blood and Transplant Research Unit. J.M.A. was supported by a Wellcome Trust Clinical Research Training Fellowship and Raymond and Beverly Sackler Scholarships. K.S.-P. was supported by an Academy of Medical Sciences/Wellcome Trust starter grant.
British Heart Foundation (FS/10/018/28193)
British Heart Foundation (FS/12/87/29899)
External DOI: https://doi.org/10.1016/j.celrep.2015.12.099
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253056
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/