Unraveling CD8+ T cell alloimmunity: Insights into the direct pathway of antigen recognition from modern experimental tools

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 can recognize self-peptide complexed to an allogeneic peptide major histocompatibility complex (MHC), termed the direct allogeneic antigen recognition pathway. Recently, 3 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, researchers showed that the MHC class I alloimmune CD8⁺ T cell response is peptide-dependent. Researchers elucidated the H-L^d QL9 allogeneic epitope and showed that reactive CD8⁺ T cells were peptide discriminating. Researchers also 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 4 donors. Through new experimental tools, these studies offer granular evidence of the mechanisms by which CD8⁺ T cells recognize allogeneic antigens and provide a framework for future approaches to selectively target them.