Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY/ABSTRACT. CD4+ T regulatory cells (Treg cells) are a minor population of lymphocytes found throughout the body. Treg cells are primarily characterized by expression of the transcription factor Foxp3 and are essential for preventing autoimmunity throughout life. Because of their ability to suppress the activity of pro-inflammatory cells, and recent success treating human diseases, Treg cells can potentially be effective in treating inflammatory bowel disease (IBD). Some of the obstacles limiting the clinical use of Treg cells include difficulties obtaining a sufficient number of cells, the inability to direct the cells to the site of inflammation, and the instability of some Treg cells under inflammatory conditions. The latter is especially true of in vitro-differentiated Treg cells (iTreg cells) that can be generated by stimulation of naïve precursors in the presence of transforming growth factor-beta (TGFß), interleukin-2 (IL-2) and retinoic acid. This approach will allow for the generation of larger numbers of Treg cells than can be isolated and expanded from peripheral blood. Moreover, such cells can be engineered to express gut antigen-specific receptors that will ultimately guide them to the inflamed intestines. This means that the only major hurdle that would remain is the well-documented instability of iTreg cells. Finding ways to overcome this limitation could therefore hasten the therapeutic use of iTreg cells. One way to address this is to first determine how Treg cell stability is achieved in nature and apply those mechanisms to the generation of iTreg cells. We have found that in the absence of T cell so-stimulation via the interaction of the inducible T cell co-stimulator (ICOS) and its ligand (ICOS ligand, ICOSL), Treg cells in the large intestine - all of which develop naturally in vivo - lose expression of Foxp3. Even in health, the intestine is considered to be in a state of ‘physiologic inflammation’ owing to the basal levels of pro-inflammatory mediators induced via interactions with the commensal microbiota. Therefore, this project will test the hypothesis that ICOSL-ICOS stimulation is essential for imprinting the phenotypic stability that promotes Foxp3+ Treg cell resilience in the presence of pro-inflammatory signals. Importantly, we have also found that iTreg cells differentiated in the absence of ICOSL rapidly extinguish expression of Foxp3, in stark contrast to their ICOSL-activated counterparts. The first objective of this proposal is to determine the possible consequences of ICOSL deficiency on the fate of in vivo derived Treg cells, providing novel insight into nature’s use of this pathway for promoting sustained expression of Foxp3 in the intestines. We will then test whether inclusion of a robust APC-derived ICOSL signal is an effective means of inducing stable microbiota antigen-specific iTreg cells that can specifically impede ongoing gut inflammation. Ultimately, this study has the potential to move us one step closer to effective iTreg cell-mediated immunotherapy for IBD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
