Direct and indirect allograft recognition: pathways dictating graft rejection mechanisms

The T cell-dependent recognition of allogeneic tissues and organs is complicated by the fact that both donor and host antigen-presenting cells can present donor antigens to host T cells. As such, these pathways result in T cells that can be restricted to either donor ('direct') or host ('indirect') major histocompatibility complex (MHC). These pathways are well recognized, but how these distinct patterns actually dictate allograft recognition is less clear. Thus, the purpose of the review is to summarize results from preclinical animal models in an attempt to clarify the distinct forms of allograft rejection dictated by these recognition pathways.

CD4 and CD8 donor MHC-restricted T cells are sufficient to reject allografts by a T-cell receptor-mediated direct ('cognate') interaction using a defined array of effector molecules. Conversely, 'noncognate' host MHC-restricted CD4 T cells must interact with intermediate host-type antigen-presenting cells and so greatly amplify the response by triggering antibody and inflammatory responses.

Importantly, 'cognate' CD4 and CD8 T cells have strikingly similar requirements for rejection, suggesting that this effector mechanism is dictated by the nature of allograft recognition rather than by T-cell subset. Conversely, 'noncognate' allograft recognition drives an increasingly appreciated role for inciting innate immunity in mediating allograft injury.