(454) Intestine-Resident Memory T Cells Are Differentially Controlled by TGF-β

Introduction/Rationale: 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 -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.