Regulatory T cells (Tregs) play an indispensible role in preventing autoimmune and chronic inflammatory diseases, such as inflammatory bowel disease (IBD), by controlling effector T cell responses. Recent studies seeking to treat human patients with exogenous Tregs have shown promise, but efficacy was limited by poor survival of the transferred Treg populations. Thus, a better understanding of the mechanisms that underlie the production of new Tregs, the maintenance of mature Tregs, and the induction of Treg function will be critical to fully exploit the therapeutic potential of Tregs in the future. Treg development in the thymus, and the subsequent homeostasis of mature Tregs in peripheral tissues, as well as induction of Treg suppressive function are all processes that are strictly dependent upon IL2. A central question is what cell subsets actually produce the IL2 needed for Treg development, homeostasis, and function? The hypothesis underlying this proposal is that thymic dendritic cells (DC) are the chief cell subset producing IL2 for Treg development, while the subsequent homeostasis of Tregs is dependent upon effector T cell- derived IL2. In support of this hypothesis, we are unable to detect IL2 mRNA in CD4 single positive thymocytes, while we can detect this message in sorted thymic DC. This application utilizes a novel Il2 floxed mouse to create conditional, cell-specific IL2 deficiency allowing us to formally test these hypotheses. Furthermore, the biological significance of IL2 production by these distinct cell subsets as it pertains to Treg homeostasis and function will be tested using an in vivo model of T cell transfer colitis. In addition to defining the cell subsets responsible for IL2 production, tis application proposes a second aim to define the mechanisms that regulate IL2 production. Our preliminary data indicate that precursors of mature Tregs in the thymus express high levels of the TNF receptor superfamily members OX40 and GITR, and thymic DC express the counter-ligands, OX40-L and GITR-L. This application will test the hypothesis that OX40 and GITR expression by Treg precursors promotes the production of IL2 by thymic DC, thereby supporting the development of mature Tregs. These studies will address the specific roles that various IL2-producing cell subsets play in governing Treg biology and provide insights into the molecular mechanisms needed to engender the development, homeostasis, and function of these critical cells. Knowledge acquired from the studies proposed in this application may aid in improving future Treg cell therapies to enhance survival and function of the transferred Treg populations. Furthermore, understanding the specific mechanisms that regulate IL2 production may also be a valuable tool for inducing endogenous IL2 production by distinct cell subsets and therefore increasing the numbers and function of endogenous Tregs in patients affected by disorders like IBD.
Inflammatory bowel disease is the result of an aberrant immune response against normally harmless bacteria or food in the gut. Regulatory T cells are a normal component of the immune system required for preventing inflammatory bowel disease. This project focuses on the development, homeostasis, and function of regulatory T cells and will provide information on how to better utilize these cells to treat human diseases like Crohn's disease or ulcerative colitis.
|Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M et al. (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15:473-81|