TCR signaling in thymic selection: Role of innate immune activation

Summary The thymus plays a critical role in preventing autoimmunity by deleting or inducing a Treg cell fate in thymocytes that react to self-antigens present in the thymus. But it is unclear how the thymus achieves tolerance to transiently expressed self-antigens, like those expressed in induced immune states such as inflammation, wound repair, and germinal center reactions. We have recently discovered that the thymus constitutively produces type I and III interferons and class switched activated B cells, beginning quite early in life. Our published and preliminary data show that these cytokines activate antigen presenting cells in the thymus environment and cause reproducible changes in the T cell repertoire selected, particularly the Treg cell repertoire. Thus, we seek to test the hypothesis that T cells need to be highly tolerant of induced immune states (inflammation, germinal centers) in order to function in those states without inducing autoimmune pathology. The proposed research will: 1) Test if thymic IFN provides T cell tolerance to interferon stimulated self-antigens, 2) Determine why IFNI/III deficient mice have a major thymic selection defect, and 3) Test if IFNIII-licensed B cells select Treg cells that regulate humoral immune responses. These aims will provide a mechanistic understanding of the source and consequences of innate immune activation in the thymus. Understanding T cell tolerance to self-antigens in immune activated states is important because many human autoimmune diseases are associated with or follow infections.