Unraveling CD8+ T Cell Alloimmunity: Insights into the Direct Pathway of Antigen Recognition from Modern Experimental Tools.

Abstract

Early experimental investigations of alloimmunity demonstrated that the T cell response against allogeneic antigens is robust and results from a high precursor frequency of responding clones. Seminal studies using cell culture-based methods led to an overall model in which CD8+ T cells are able to recognize self-peptide complexed to allogeneic peptide MHC, termed the direct allogeneic antigen recognition pathway. Recently, three groups used modern experimental approaches, including MHC class I tetramers, to further investigate the nature of direct allogeneic antigen recognition by CD8+ T cells in mice and humans. In a model of liver-induced transplant tolerance, Son et al showed that the MHC class I alloimmune CD8+ T cell response is peptide dependent. Cohen et al elucidated the H-Ld QL9 allogeneic epitope and showed that reactive CD8+ T cells were peptide discriminating. Zhang et al engineered artificial antigen presenting cells to show that human alloreactive CD8+ T cells against HLA-A antigens were MHC restricted, and demonstrated a public HLA-A2 CD8+ T cell response in four donors. Through new experimental tools, these studies offer granular evidence of the mechanisms by which CD8+ T cells recognize allogeneic antigen, and provide a framework for future approaches to selectively target them.