Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+25+ immunoregulatory T cells

CD4(+)25(+) T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-A beta (b) mice, major histocompatibility complex (MHC) class II I-A(b) expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DM alpha -deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4(+)25(+) T cells are present in the thymus and periphery of K14-A(beta)(b) and H2-DM alpha -deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4(+)25(-) effector T cells. In contrast, CD4(+)25(+) T cells from MHC class II-deficient mice do not suppress responder CD4(+) T cells in vitro or in vivo. Thus, development of regulatory CD4(+)25(+) T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4(+)25(+) T cells in K14-A(beta)(b) and H2-DM alpha -deficient mice suggests that a subset of CD4(+)25(+) T cells is subject to negative selection on hematopoietic antigen-presenting cells.