👤 Inta Gribonika

Intestinal immunity defends against enteric pathogens, mediates symbiotic relationships with the resident microbiota, and provides tolerance to food antigens, safeguarding critical nutrient absorption and barrier functions of this mucosal tissue. Despite the abundance of tissue resident activated T cells, their contributions to these various roles remains poorly understood. Here, we identify a dominant population of IL-10 producing, T-bet expressing CD4+ Tr1 T cells, residing in the small intestinal lamina propria at homeostasis. Remarkably, these intestinal Tr1 cells emerge at the time of weaning and accumulate independently of the microbiota displaying similar abundance, function and TCR repertoire under germ-free conditions. Instead, the small intestinal T-bet+ Tr1 program is driven and shaped by dietary antigens, and accumulates in a cDC1-IL-27 dependent manner. Upon activation, these cells robustly express IL-10 and multiple inhibitory receptors, establishing a distinct suppressive profile. Altogether, this work uncovers a previously unappreciated dominant player in homeostatic small intestinal immunity with the potential to play critical suppressive roles in this tissue, raising important implications for the understanding of immune regulation in the intestine. Establishing immunological tolerance to self and environmental antigens is critical to preserve tissue homeostasis and function. In the intestine, both dietary and microbiota derived antigens are routinely encountered by the immune system, which deploys a variety of mechanisms to maintain tolerance to these innocuous antigens. Understanding how immunological tolerance is established is critical, a when this process goes awry it can lead to severe inflammatory and autoimmune diseases such as food allergy and inflammatory bowel disease. However, how tolerance is established in the intestine is still poorly understood. In this study we describe a novel dominant T cell population in the small intestine shaped by dietary components with the potential to play important roles in immune tolerance at this site. back # IntroductionBarrier surfaces such as the gut and skin represent the first line of defense against the environment. These organs must strike a delicate balance between providing protection against environmental and infectious agents, maintaining tissue function, and establishing a homeostatic symbiotic relationship with resident microbes collectively known as the microbiota (1). The immune system plays a critical role in establishing these dynamic and carefully regulated relationships, as evidenced by the large number of immune cells present at these sites. Of particular note, activated T cells are very abundant at barrier tissues, where they orchestrate immune effector functions geared towards these varied tasks (1, 2). In the small intestine, the intraepithelial compartment harbors innate like natural CD8aa⁺ IELs, many of which are self reactive; as well as CD4⁺CD8aa⁺ and CD8ab⁺ IELs responding to dietary and microbial antigens (3). The underlying lamina propria (SILP) harbors predominantly CD4⁺ T cells, which participate in responses to commensal-derived and dietary antigens (2, 4). Despite the abundance of small intestinal CD4 T cells, only a handful of cognate immune interactions focusing on Type 17 and T regulatory helper subsets have been described. Thus, whether immune responses in this tissue are truly limited to a small number of antigenic triggers and effector functions remains to be fully elucidated. The small number of gut homeostatic CD4 T cell responses described thus far have been shown to primarily respond to specific commensal bacteria or dietary antigens (1, 2, 5-8): Among other examples, SFB induces cognate Th17 cells in the small intestine (9, 10), a consortium human commensal bacteria induces CD8b⁺ cells in the colon (11), and Show less