Foxp3 + regulatory T cells in peripheral tissues (pT regs ) are instrumental in limiting inflammatory responses to non-self antigens. Within the intestine, pT regs are located primarily in the lamina propria, while intraepithelial CD4 + T cells (CD4 IELs ), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we show distinct cell dynamics of intestinal T regs and CD4 IELs . Upon migration to the epithelium, T regs lose Foxp3 and convert to CD4 IELs in a microbiota-dependent fashion, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pT regs and CD4 IELs perform complementary roles in the regulation of intestinal inflammation. These results reveal intra-tissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine.The gut mucosa is exposed to large amounts of both harmless and potentially pathogenic stimuli on a daily basis, hence diverse immune regulatory mechanisms must operate to avoid inflammatory diseases (1). Peripheral Foxp3-expressing regulatory T cells (pT regs ) mediate suppression of a variety of immune cells and actively prevent inflammatory bowel diseases and food allergies (2-7). Similar to pT regs , Foxp3 − CD8αα + CD4 + intraepithelial lymphocytes (CD4 IELs ) depend on retinoic acid (RA) and transforming growth factor (TGF)-β signaling for their development and also have anti-inflammatory properties (4,(8)(9)(10)(11)(12)(13). However, while CD4 IELs accumulate in the intestinal epithelium, very few total T regs (including pT regs or thymically-derived T regs ) can be found at this site ( fig. S1A and B fig. S2A). Because previous studies have demonstrated that the majority of "ex-Foxp3" cells in the steady state were derived from uncommitted precursors that transiently upregulated Foxp3 (18), we also performed fate mapping after pulse-labeling iFoxp3 Tomato mice with tamoxifen (14), a strategy more likely to target bona fide T regs (19). Nevertheless, while stable Foxp3 expression was again observed in several peripheral tissues examined, over 50% of Tomato + CD4 + T cells that accumulated in the small intestine and almost 10% in the large intestine epithelium isolated from iFoxp3 Tomato mice no longer expressed Foxp3 fives weeks post tamoxifen administration ( fig. S2B and C). The contribution of Tomato + cells to the CD8αα + and CD8αβ + CD4 IEL pools was roughly 10% and 25%, respectively ( fig. S2D). Consistent with a ThPOK-dependent process, ex-T regs that underwent IEL differentiation showed low levels of ThPOK ( fig. S2E). These results indicate that a substantial proportion of intestinal T regs physiologically convert to CD4 IELs .Commensal bacteria play a major role in the induction of lamina propria pT regs in the large intestine (3,(5)(6)(7)20). In contrast, we observed an increased frequency of pT regs (Neuropilin-1 − Foxp3 + ) in the small intestinal epithelium isolated from germ-free (GF) mice when compared to...

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Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103−CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

F. saccharivorans decreased in correlation to UC activity and suppresses intestinal inflammation. These results suggest that F. saccharivorans could lead to a novel UC treatment.

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