Identification of a Highly Functional Effector CD8+ T Cell Program After Transplantation in Mice and Humans
Cohen, G. S.; Freibaum, J. S.; Leathem, R. P.; Hatano, R.; Morimoto, C.; Krummey, S. M.
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T cell mediated allograft rejection leads to early graft loss for kidney transplant patients. To better understand the mechanism by which T cells mediate rejection, we investigated the fate and function of graft-specific CD8+ T cells expressing the activated isoform of CD43 in mice and humans. Agonism of CD43 1B11 in vitro induced CD8+ T cell proliferation in the presence of sub-threshold antigen stimulation, and CD43 1B11 mAb treatment in vivo overcame costimulation-blockade induced tolerance to skin grafts. Relative to CD43 1B11- populations, CD43 1B11+ CD8+ T cells maintained high T-bet expression along with stem-like molecules IL-7R and TCF-1 at both effector and memory timepoints, and were more persistent following adoptive transfer. In kidney transplant patients, graft-infiltrating CD8+ T cells that expressed CD43 and the glycosyltransferase GCNT1 had an effector phenotype that includes high expression of IFNG, ICOS, and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 mAb clone defined antigen-experienced cytokine-producing CD8+ T cells. In sum, these data support a progressive differentiation model by which highly proliferative effector CD43 1B11+ CD8+ T cells infiltrate allografts also efficiently persist into memory after antigen clearance.
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