Towards a structural understanding of alloreactivity

Abstract

One of the most thoroughly documented, yet paradoxical responses in immunology occurs in what is known as the mixed leukocyte culture (MLC). Typically, peripheral blood mononuclear cells proliferate vigorously when presented with allogeneic PBL (peripheral blood lymphocytes), but not with autologous or syngeneic cells. MLC reactivity as an in vitro measure of histocompatibility can be correlated with graft rejection or graft versus host disease. The paradoxical aspect of alloreactivity is manifested in light of recent experiments, which demonstrate that T cells normally respond to antigens in the context of autologous MHC molecules (Zinkernagel and Doherty, 1979; Rosenthal and Shevach, 1973; Shevach and Rosenthal, 1973). T-cell recognition is thus said to be self-restricted. Furthermore, we also know from these same experiments that allogeneic antigen-presenting (APC) cells are essentially incapable of presenting antigen to appropriately primed T ceils. How then can T cells, which normally see antigen in a self-restricted fashion, also recognize allogeneic MHC molecules in the MLC ? Numerous theories have sought to describe alloreactivity as somehow qualitatively or quantitatively different from self-restricted recognition. However, we would like to contend that allorecognition is fundamentally and qualitatively no different from self-restricted recognition at the structural level. In this context, we argue that an appreciation of the structural basis of allorecognition is a prerequisite to developing effective, antigen-specific therapeutic strategies for ameliorating graft rejection and graft versus host disease.