Intestine-Resident Memory T Cells Are Differentially Controlled by TGF-β 2258442

Abstract Introduction Tissue-resident memory T cells (TRM) provide the first line of defense for the intestinal mucosa. It is well known that TGF-β signaling is required for the formation of intestine-resident memory T cells. However, the function of TGF-β signaling in intestinal TRM at the memory phase is not completely known. Methods An inducible TGF-βR KO mouse model (TβRII floxed) was used to examine the role of TGF-β signaling toward the homeostasis of IEL and LP TRMs, specifically, CD69+CD103+ and CD69+CD103- TRM populations. TRM from IEL and LP were isolated, fluorescently stained and analyzed by flow cytometry. Bulk RNA-seq were performed using FACS-sorted CD69+CD103+ and CD69+CD103- TRM from the LP of WT and KO mice. Differentially regulated genes were compared using R tools. Results TGF-β signaling differentially controls intestine TRM in a subset-dependent and location-dependent manner. Specifically, in the intraepithelial lymphocyte (IEL) compartment, inducible deletion of TGF-βR leads to a slight but significant reduction of CD69+CD103+ cells. The remaining cells are highly enriched for deletion escapers. In contrast, we detected a dramatic increase of CD69+CD103- TRM in the lamina propria (LP) upon TGF-βR deletion. Importantly, the TGF-βR-/- CD69+CD103- cells maintain their tissue residency without leaving the tissue. Functionally, we observed that TGF-βR-/- CD69+CD103- TRM in the LP exhibited a significant reduction of a panel of innate immune defense genes, such as lysozyme and α-defensins, suggesting that continuous exposure to TGF-β signaling is not only required for the maintenance of CD69+CD103+ TRM, but also for the promotion of local innate immune defense function. Conclusion Our data showed that TGF-β signaling is critical to CD103+ IEL formation and also influential toward TRM localized in LP. Its presence or absence potentially regulates the immune response of TRM in local environment. Funding Source NIH Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)