Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance

Abstract

Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity, yet the identity of cells involved remains elusive. Here we show that antigen expression in a minor fraction of medullary thymic epithelial cells leads to deletion of specific CD4 T cells. Strikingly, this deletion is not dependent on cross-presentation by hemopoietic antigen-presenting cells, which have been ascribed a predominant role in negative selection. By contrast, when the same antigen enters the thymus via the blood stream, negative selection is strictly dependent on antigen presentation by hemopoietic cells. These findings imply that the (re)-presentation of "self" by thymic stromal cells is non-redundant, and that different thymic antigen-presenting cells instead cover complementing sets of self-antigens, thus maximizing the scope of central tolerance.