The enigmatic impact of donor T cell subsets on the therapeutic efficacy of tolerogenic protocols for transplant rejection

Abstract

Abstract Costimulation blockade (CoB) regimens are a promising immunomodulatory strategy to prevent transplant rejection. However, we are learning that their efficacy is affected by multiple factors. Recent reports have started highlighting the unexpected capacity of passenger donor lymphocytes to enhance the recipient’s anti-graft response. New studies are necessary to understand this novel phenomenon and how it can affect the induction of transplant tolerance. In this study we assessed if T lymphocytes contained in the donor specific transfusion (DST) inoculum, used in combination with anti-CD154 (MR1) as CoB regimen, impact the regulation of mouse skin transplant rejection. When T cells were depleted from the DST, transplant survival was almost doubled. T cell subset-depletion studies indicated, unexpectedly, that donor CD8 T cells were responsible for limiting the efficacy of the tolerogenic regimen. Even more surprisingly, the presence of CD4 T cells in DST induced a remarkable improvement in transplant survival, beyond that observed with full T cell depletion. Ongoing experiments are determining the correlation between donor T lymphocytes and variations in humoral and cellular anti-donor responses. Overall, these data reveal the existence of a novel and unexpected opposing role of donor passenger lymphocytes that significantly modifies the therapeutic efficacy of DST+MR1 based regimens: a deleterious role for donor CD8, and a beneficial one for CD4 T cells. Identification of the specific mechanisms through which these divergent modulations of the anti-donor alloresponse are exerted could suggest significant changes in how we should approach immunoregulation, both experimentally as well as clinically.