Alloanergization of human T cells results in expansion of alloantigen-specific CD8+CD28- suppressor cells

Abstract

Allostimulation with concurrent costimulatory blockade induces alloantigen-specific hyporesponsiveness in responder T cells ("alloanergization"). Alloanergized responder cells also acquire alloantigen-specific suppressive activity, suggesting this strategy induces active immune tolerance. While this acquired suppressive activity is mediated primarily by CD4+FOXP3+ cells, other cells, most notably CD8+ suppressor cells, have also been shown to ameliorate human alloresponses. To determine whether alloanergization expands CD8+ cells with allosuppressive phenotype and function, we used mixed lymphocyte cultures in which costimulatory blockade was provided by belatacept, an FDA-approved, second-generation CTLA-4-immunoglobulin fusion protein that blocks CD28-mediated costimulation, as an in vitro model of HLA-mismatched transplantation. This strategy resulted in an eightfold expansion of CD8 +CD28- T cells which potently and specifically suppressed alloresponses of both CD4+ and CD8+ T cells without reducing the frequency of a range of functional pathogen-specific T cells. This CD8-mediated allosuppression primarily required cell-cell contact. In addition, we observed expansion of CD8+CD28- T cells in vivo in patients undergoing alloanergized HLA-mismatched bone marrow transplantation. Use of costimulatory blockade-mediated alloanergization to expand allospecific CD8+CD28- suppressor cells merits exploration as an approach to inducing or supporting immune tolerance to alloantigens after allogeneic transplantation. The investigators use in vitro costimulatory blockade-mediated alloanergization to expand CD8+CD28-FOXP3 + suppressor cells with allosuppressive function, and provide in vivo evidence suggesting the feasibility of their use as a tolerance-inducing cell therapy. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.