Insights into MHC class II regulation of T cell responses (IRM15P.463)

Abstract

Abstract Besides their ability to present antigenic peptides and stimulate antigen-specific T lymphocytes, MHC class II (MHCII) molecules have also been implicated in the regulation of ensuing T cell responses. However, the substance of MHCII regulation remains elusive to this day. Defining the variables of this phenomenon appears to be critical for developing rational therapeutic approaches. Using models in which MHCII regulation has been demonstrated, we have revisited the concept by evaluating the impact of MHCII-restricted CD4 regulatory T cells (Tregs) on T cell reactivity to either allogeneic or self-antigens. Studies performed in vitro and in vivo showed that graft host Tregs specific to donor MHCII peptides / host MHCII complexes promoted T cell tolerance of fully allogeneic grafts. These pMHCII complexes - hereafter called TLo - were also involved in Treg-mediated suppression and in initial host Treg activation by graft MHCII. Extending these observations to Treg biology of normal animals, we have also shown that substantial amounts of TLo complexes selectively decorate antigen-presenting cells (APC) from the thymic medulla and participate in the differentiation of suppressive, TLo-specific Treg cells. Together these results suggest that, under steady-state conditions, MHCII genes regulate T cell responses by 1) generating self-TLo complexes on thymic APC to direct thymic Treg development and 2) modulating peripheral T cell activation via TLo-specific Tregs.