STING controls T cell memory fitness during infection through T cell-intrinsic and IDO-dependent mechanisms
Michael J. Quaney, Curtis J. Pritzl, Dezzarae Luera, Rebecca J. Newth, Karin M. Knudson, Vikas Saxena, Caitlyn Guldenpfennig, Diana Gil, Chris S. Rae, Peter Lauer, Mark A. Daniëls, Emma Teixeiro
Abstract
Stimulator of interferon genes (STING) signaling has been extensively studied in inflammatory diseases and cancer, while its role in T cell responses to infection is unclear. Using Listeria monocytogenes strains engineered to induce different levels of c-di-AMP, we found that high STING signals impaired T cell memory upon infection via increased Bim levels and apoptosis. Unexpectedly, reduction of TCR signal strength or T cell-STING expression decreased Bim expression, T cell apoptosis, and recovered T cell memory. We found that TCR signal intensity coupled STING signal strength to the unfolded protein response (UPR) and T cell survival. Under strong STING signaling, Indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition also reduced apoptosis and led to a recovery of T cell memory in STING sufficient CD8 T cells. Thus, STING signaling regulates CD8 T cell memory fitness through both cell-intrinsic and extrinsic mechanisms. These studies provide insight into how IDO and STING therapies could improve long-term T cell protective immunity.