Fibroblasts as a source of self-antigens for central immune tolerance.

Nitta, Takeshi; Tsutsumi, Masanori; Nitta, Sachiko; Muro, Ryunosuke; Suzuki, Emma C; Nakano, Kenta; Tomofuji, Yoshihiko; Sawa, Shinichiro; Okamura, Tadashi; Penninger, Josef M; Takayanagi, Hiroshi

Fibroblasts are one of the most common but also neglected types of stromal cells, the heterogeneity of which underlies the specific function of tissue microenvironments in development and regeneration. In the thymus, autoreactive T cells are thought to be negatively selected by reference to the self-antigens expressed in medullary epithelial cells, but the contribution of other stromal cells to tolerance induction has been poorly examined. In the present study, we report a PDGFR+ gp38+ DPP4- thymic fibroblast subset that is required for T cell tolerance induction. The deletion of the lymphotoxin β-receptor in thymic fibroblasts caused an autoimmune phenotype with decreased expression of tissue-restricted and fibroblast-specific antigens, offering insight into the long-sought target of lymphotoxin signaling in the context of the regulation of autoimmunity. Thus, thymic medullary fibroblasts play an essential role in the establishment of central tolerance by producing a diverse array of self-antigens.