Transplantation Elicits a Clonally Diverse CD8⁺T Cell Response that is Comprised of Potent CD43⁺Effectors

Abstract

CD8+ T cells mediate acute rejection of allografts, which threatens the long-term survival of transplanted organs. After antigen encounter, CD8+ T cells differentiate into effector populations that traffic to allografts and exert cytotoxic functions. The phenotype of effector CD8+ T cells after transplantation is not well-understood. We characterized the use of an allogeneic MHC Class I tetramer comprised of the ubiquitous self-peptide QL9 presented by H-2Ld, to assess anti-donor H-2b CD8+ T cells. T cells specific for this epitope were found at an elevated precursor frequency in naive mice relative to model antigen and viral epitopes. After grafting of allogeneic H-2d skin, Ld QL9+ T cells divided and differentiated into effector CD8+ T cells, but only weakly increased in numbers. Antigen-specific effector CD8+ T cells downregulated CD127, but a low frequency expressed the effector marker KLRG-1. Using high-parameter flow cytometry, we found that expression of the activated glycoform of sialophorin CD43 increased at acute timepoints. Relative to CD43- populations, effector CD43+ CD8+ T cells displayed potent effector phenotype and functionality, including GranzymeB production, cytokine production, and accelerated graft rejection. In the presence of costimulation blockade with CTLA-4 Ig, CD43+ effector T cells maintained high expression of the costimulatory receptor ICOS. ICOS blockade in conjunction with CTLA-4 Ig prolonged graft survival. These data demonstrate that the graft-specific CD8+ T cell response has a distinct response profile relative to anti-pathogen responses and that CD43 and ICOS are critical surface receptors that define potent effector CD8+ T cell populations that form after grafting. These findings have implications for the selective targeting of CD8+ T cells that mediate transplant rejection.