How T cells recognize alloantigen: evidence for two pathways of allorecognition.

During allograft rejection, both allorecognition pathways seem to be effective. The direct pathway, where T-cell receptors directly recognize intact allo-MHC with or without bound peptides on the surface of target cells, accounts for most of the cytotoxic T cell function. The indirect pathway in contrast, where T-cell receptors recognize MHC allopeptides after processing and presentation by self APCs, may lead to the activation of T helper cells which secrete cytokines and provide the necessary signals for the growth and maturation of effector cytotoxic T lymphocytes and B cells leading to allograft rejection. The role of the indirect pathway is supported by the findings that mouse skin transplants from a class II deficient donor can be rejected involving CD4+ self-restricted T-cell recognition of donor antigen. In addition, rats primed by class I MHC peptides do reject skin grafts as well as renal allografts in an accelerated fashion. Studies showing that synthetic class II peptides can also be used to tolerize animals for a subsequent renal transplant further underline the importance of this self restricted recognition of allo-MHC. More studies are needed to better define the contribution of this self-restricted T cell recognition of processed allo-MHC to the rejection process in particular in regard to its suggested role in chronic allograft failure as well as to its susceptibility to therapeutic regimens in organ transplant recipients.