Graduate Student Vanderbilt University Nashville, Tennessee, United States
Abstract Text: There is an urgent need for improved vaccine adjuvants, as current FDA-approved adjuvants are generally ineffective at inducing T cell-mediated immunity necessary for many anti-viral or anti-tumor responses. Nucleic acid agonists have emerged as potential adjuvants that stimulate T cell responses by activating nucleic acid sensors, including the Stimulator of Interferon Genes (STING), to induce antiviral Type I Interferon (IFN-I) production by innate immune cells. Importantly, STING is also highly expressed in T cells and can be activated by infection and cell-stress (e.g. hyperthermia) induced self-DNA leakage. However, the role of STING in regulatory T cells (Tregs) is not well-understood. Furthermore, although heat is a hallmark of inflammation, the effects of fever on Tregs remain unknown. Here, we report that STING induces a pro-inflammatory phenotype in murine Tregs, which normally exert anti-inflammatory, immunosuppressive functions. At physiological and fever-range temperatures (FRT, 39.5°C), STING activation significantly decreased Treg viability and expression of Treg markers CD25 and FoxP3 and immunosuppressive proteins TGF-β and CTLA-4. Surprisingly, STING induced high levels of IFN-I, suggesting that STING can promote antiviral responses by Tregs. Additionally, FRT decreased Treg suppressive function and significantly enhanced the effects of STING. In summary, these data provide the first evidence that STING agonists can induce IFN-I production by Tregs, suppress their anti-inflammatory phenotype, and that these effects are potentiated by fever. Thus, this study motivates further investigation of Treg function at FRT and suggests the potential for Treg-targeted STING agonists as a method to improve T cell responses to vaccines and immunotherapies.
