Abstract
Immune homeostasis in the gut-associated lymphoid tissues (GALT) is critical to prevent the development of inadvertent pathologies. B cells, as the producers of antibodies and cytokines, play an important role in maintaining the GALT homeostasis. However, the mechanism by which B cells specifically direct their responses toward non-self-antigens and become ignorant to self-antigens in the GALT is not known. Therefore, we developed what we believe to be a novel mouse model by expressing duck egg lysozyme (DEL) in gut epithelial cells in presence of HEL-reactive B cells. Notably, we observed a transient activation and rapid deletion of self-reactive B cells in Peyer’s patches and mesenteric lymph nodes upon self-antigen exposure. The survival of self-reactive B cells upon exposure to their self-antigen was partially rescued by blocking receptor editing but could be completely rescued by stronger survival signal, such as ectopic expression of BCL2. Importantly, rescuing the self-reactive B cells promoted production of autoantibodies and gut inflammation. Mechanistically, we identify a specific activation of TGF-β signaling in self-reactive B cells in the gut and a critical role of this pathway in maintaining peripheral tolerance. Collectively, our studies describe functional consequences and the fate of self-reactive B cells in GALT and provide potentially novel mechanistic insights governing self-tolerance of B cells in the gut.
Authors
Ashima Shukla, Cindi Chen, Julia Jellusova, Charlotte R. Leung, Elaine Kao, Numana Bhat, Wai W. Lin, John R. Apgar, Robert C. Rickert
Histology scores and criteria
