Harnessing temperature-dependent STING signaling to reprogram regulatory T cells and enhance effector T cell immunity.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B713
Abstract ID: 5584

Presenting Author:
Rachael C Smith , Graduate Student at Vanderbilt Univ.

Abstract:

The cGAS-STING pathway plays a critical role in immune surveillance through its capacity to sense aberrantly localized DNA in the cytosol caused by infection, cancer cell death, or cell stress-induced self-DNA leakage. STING pathway activation ultimately results in the production of Type I Interferons (IFN-I) and other inflammatory cytokines that stimulate T cell immunity. However, the T cell-intrinsic effects of STING agonists have been underexplored, especially in regulatory T cells (Tregs), which have an opposing but crucial role in suppressing excessive inflammation. Unexpectedly, we have found that STING activation repolarizes Tregs to IFN-I producing Th1/Th9-like cells with enhanced antitumor function and reduced oxidative metabolism and suppressive capacity. Inflammation can also coincide with heat (i.e. fever-range temperature, FRT, 39°C), which can cause nuclear or mitochondrial self-DNA leakage, yet the effects of FRT on STING in Tregs are unknown. We were surprised to find that FRT strongly potentiates the effects of STING activation in Tregs and that FRT appears to prime cGAS/STING signaling. Together, our initial data suggest a novel axis linking FRT to STING signaling in inhibiting Treg immunosuppressive function and in promoting Treg transdifferentiation to inflammatory effector-like T cells. These exciting findings motivate further investigation to dissect the mechanisms intertwining STING activation and FRT and their effect on Treg function and metabolism.