Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance

Abstract

The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche.

Thymically-derived Foxp3+ regulatory T cells are the primary regulators of type 1 diabetes in the non-obese diabetic mouse model

“…These RORγt+ Tregs are induced by the presence of complex microbiota and provide anti-inflammatory functions [50] and have been shown to have a distinct repertoire [51]. For example, RORγt + pTregs responsive to the short-chain fatty acid (SCFA) butyrate are generated in the gut [42] where they function to establish border-dwelling bacteria that protect against microbial exposure and normal metabolite profiles [43]. Therefore, we hypothesized that there would be a reduction in the Helios − and RORγt + pTreg populations in NOD CNS1 −/− females.…”

“…The gut microbiome might be linked to T1D due to the fact that the pLN is also a draining site for microbial antigens [59], and autoreactive cells have also shown cross-reactivity between microbial antigens and islet antigens [60,61]. In fact, recent characterization of the B6 CNS1 −/− mouse directly revealed that defects in gut pTreg generation alter gut microbiome colonization [42,43]. Since there is a change in gut Tregs in both NOD CNS1 −/− models generated, the ability to observe a similar disease phenotype in our NOD CNS1 −/− model might be masked by differences in gut microbiome composition.…”

“…B6 CNS1 −/− blocked increases in Treg percentages in peripheral tissues with age, resulting in Th2-mediated pathology in the lungs and intestinal tract [41]. Continued characterization of the B6 CNS1 −/− mouse revealed defects in pTreg generation and gut microbiome colonization in CNS1 −/− mice [42,43] as well as in maternal-fetal tolerance [44].…”

The human small intestine contains two subsets of regulatory Foxp3+ CD4+ T cells with very different life span and functional properties

“…Intestinal Tregs therefore appear well suited to avoid unwanted immune reactions to such ubiquitous antigens (1,2,4). As can be expected, the majority of Tregs in the mouse colon are microbial-specific (5)(6)(7), whereas most Tregs in the mouse SI respond to food antigens (4).…”

Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

“…For example, colonization by a subset of Clostridia enhanced anti-inflammatory phenotypes in mice 3 , and enrichment in specific members of the Bacteroides and Parabacteroides genera induced CD8+ T cell responses and anticancer activity in mice and marmosets 4 , as well as correlating with the abundance of these immune effectors in humans 5 . A multitude of experiments in mice have allowed for the determination of mechanisms by which intestinal mucosal-associated bacteria affect host physiology at the epithelial interface and systemically throughout their host 6,7 .…”