CD4+ T cell recognition of alloantigen is the central and primary event which leads ultimately to graft rejection. It is now clear that there are two distinct, but not necessarily mutually exclusive, pathways of allorecognition. In the "direct" pathway T cells recognize intact allo-MHC molecules on the surface of donor cells. In the "indirect" pathway T cells recognize processed alloantigen presented as peptides by self APCs. Antigen recognition provides signal 1 to the T cell via the TCR. T cells then receive a second costimulatory signal provided by interactions of cell surface receptors on the T cell with their ligands, typically on antigen-presenting cells (APCs), although these ligands can also be expressed on parenchymal cells. Positive costimulatory signals are pivotal in determining whether recognition of antigen by T cells leads to full T cell activation. In addition, recent findings indicate that regulation of immune responses may be achieved by the expression of inhibitory costimulatory molecules on APCs and peripheral tissues that mediate negative costimulatory signals to the T cell. Therefore, the ultimalte fate of T cells and in turn immune responses appear to be mediated, at least in part, by the interplay between positive and negative T cell costimulatory pathways.
This lecture addresses novel concepts of transplantation immunobiology with special emphasis on T cell alloimmunity and regulation.