Journal of Clinical Investigation [IF:13.251] Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells DOI: 10.1172/JCI98929 Abstract & Authors 展開 Abstract:
Immunological tolerance to environmental factors such as intestinal bacteria and food antigens is an active, multilayered process, and its breakdown leads to hyperactivation of mucosal T and B cells and subsequent development of intestinal pathologies (1–3). Successful dietary intervention therapies in patients suffering from celiac disease, food allergies, and inflammatory bowel disease (IBD) demonstrate that diet contains immunologically relevant antigens (4–6). Yet, our understanding of diet-specific immune reactivity is largely derived from T cell receptor (TCR) transgenic mice and model antigens where tolerance mechanisms comprising clonal anergy, deletion, and induction of regulatory T cells (Tregs) have been shown (7–9). These data reveal that the contribution of clonal anergy/deletion versus active suppression by Tregs depends on type, dose, and frequency of applied antigens. Even though the vast majority of peripheral Tregs (pTregs) in the lamina propria (LP) of the small intestine is induced by normal food, oral tolerance is still intact if functional Treg levels are strongly reduced (10, 11).Although the LP is not considered a typical site of immune induction, Peyer patches (PPs) are specialized lymphoid follicles known for effective stimulation of B and T cells by luminal antigens. Surprisingly, little attention has been paid to their role in tolerance against dietary antigens. This might be due to controversial findings showing, on the one hand, that tolerance occurs in PP-deficient mice and, on the other hand, that PPs are required for oral tolerance (12–15).Here, we investigated the occurrence of diet-activated T cells in various tissues and characterized their phenotype and fate. We observed that recognition of dietary antigens is essential for the cellular and functional maturation of the small intestine, including generation of Tfh cells and IgA production. In the healthy murine and human gut, food-activated CD4+ T cells in PPs exhibited a proapoptotic phenotype characterized by the transcription factor Helios and the programmed cell death protein 1 (PD-1). In contrast, low Helios expression and reduced apoptosis were observed in PP CD4+ T cells of patients with IBD, suggesting that activation and subsequent death of food-reactive T cells is a hallmark of intestinal homeostasis.
First Authors:
Alexander Visekruna Correspondence:
Ulrich Steinhoff All Authors:
Alexander Visekruna,Sabrina Hartmann,Yasmina Rodriguez Sillke,Rainer Glauben,Florence Fischer,Hartmann Raifer,Hans Mollenkopf,Wilhelm Bertrams,Bernd Schmeck,Matthias Klein,Axel Pagenstecher,Michael Lohoff,Ralf Jacob,Oliver Pabst,Paul William Bland,Maik Luu,Rossana Romero,Britta Siegmund,Krishnaraj Rajalingam,Ulrich Steinhoff Article2019-04-02
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