STING controls T cell memory fitness during infection through T cell-intrinsic and IDO-dependent mechanisms

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 3; p. e2205049120
• Main Authors: Quaney, Michael J, Pritzl, Curtis J, Luera, Dezzarae, Newth, Rebecca J, Knudson, Karin M, Saxena, Vikas, Guldenpfennig, Caitlyn, Gil, Diana, Rae, Chris S, Lauer, Peter, Daniels, Mark A, Teixeiro, Emma
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17-01-2023
• Subjects: Apoptosis; BIM protein; Biological Sciences; CD8 antigen; CD8-Positive T-Lymphocytes; Cell survival; Fitness; Immunological memory; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Infections; Inflammatory diseases; Listeria monocytogenes; Lymphocytes; Lymphocytes T; Memory cells; Memory T Cells; Protein folding; Receptors, Antigen, T-Cell - genetics; Signal strength; Signal Transduction; Signaling; Stimulators; T cell receptors; Tryptophan 2,3-dioxygenase; STING; TCR; CD8 T cell memory
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2205049120

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
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.