by Christina Crowe
The gastrointestinal tract is home to trillions of microorganisms where they exist peacefully in a healthy individual, performing important functions in metabolism, nutrition and protection from disease-causing organisms. Our immune system senses the microbiota but doesn't respond to it in an inflammatory manner, though in immune-mediated diseases of the GI system such as Crohn’s Disease and Ulcerative Colitis, CD4+ T cells over-react to components of the gut microflora and can induce inflammation and tissue damage. However, a subset of CD4+ T cells known as regulatory T cells or Tregs, can prevent autoreactive immune responses and a secreted protein, IL-10, is the principal restraining factor.
Robin Hatton, Ph.D., Associate Professor, Anatomic Pathology, along with Casey Weaver, M.D., Wyatt and Susan Haskell Endowed Chair for Medical Excellence, recently received a dual-primary investigator R01 grant to study mechanisms controlling the development and function of intestinal eTreg cells. The grant, funded by the National Institutes of Allergy and Infectious Disease (NIAID), totals $3.6 million over five years. Studies proposed in this award aim to define the cellular and molecular cues that direct the development of these IL-10–producing cells, with a long-term goal of identifying interventions to curb pathogenic immunity to the microbiota in human inflammatory bowel disease (IBD).
Hatton and Weaver’s lab have long had an interest in the regulation of IL-10. Numerous cells in the body can make it, but Tregs are the main source of IL-10 in the large intestines. Underscoring its central role in gut health is that humans with defective IL-10 signaling acquire severe IBD and similarly, mice deficient in IL-10 spontaneously develop intestinal inflammation.
In the gut, Tregs develop in stages based on environmental cues. Central Tregs or cTregs surveil their surrounding and, upon sensing inflammation, they change and through specific signals Hatton’s team defines in the grant, they become IL-10-expressing eTregs.
“eTregs, at least in mouse models, are particularly potent in quelling IBD,” Hattonsays. “We can experimentally induce colitis in a mouse and then deploy eTreg cells to effectively suppress the inflammation.”
This study builds on research pioneered by one of the lab’s Medical Scientist Training Program (MSTP) students Emma Dean, who, Hatton says, discovered a new role for interleukin-2 (IL-2) in the development of IL10-expressing eTregs.
“cTreg development and maintenance in the gut is dependent on signals induced by the cytokine IL-2, and during her thesis work Emma found that Treg acquisition of IL-10 expression requires a second “hit” of IL-2,” Hatton explains. “She also discovered that cues from a tumor necrosis factor receptor superfamily (TNFRSF) member, DR3, augments IL-2-signaling in cTregs and promotes eTreg development.”
By focusing on how DR3 modulates Treg-IL-2 signaling and how it regulates development of IL-10-producing eTregs, this grant aims to identify the mechanisms that underlie the eTreg developmental and suppressive programs to inform novel therapeutic approaches in reversing intestinal inflammatory disease.
The Hatton-Weaver team posits that the TNF receptor, DR3, makes the Tregs more responsive to IL-2 and acts in essence as a sensor for inflammation being caused by IL-2 producing activated CD4 T cells. They will use a novel method for generating stable, colitis-curing Treg cells ex vivo; new approaches for efficient gene knock-downs in primary T cells; and new gene-targeted mouse models to define mechanisms governing the convergence of the DR3/IL-2 signaling pathways in controlling the transcriptional regulation of IL-10 and the eTreg program.
“We expect that results from these studies will establish new biological paradigms and will reveal pathways to curb pathogenic immunity to the microbiota in IBD,” Hatton says. “Clinical trials treating IBD patients with their own ex vivo expanded Tregs are currently ongoing, and we believe that our system that amplifies IL-10 expression from Tregs via the IL-2 receptor/DR3 signaling axis has extraordinary potential to greatly improve the efficacy of autologously transferred Tregs in ameliorating disease.”