STAT1 restrains peripheral naive CD8+ T cell responsiveness to homeostatic cytokines by regulating mTORC1 signaling

Abstract

Abstract Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, South Korea In a steady-state, naïve CD8+ T cells are kept to be quiescent in response to homeostatic cues such as self-ligands and cytokines while preserving a robust responsiveness to foreign antigens. Although such a steady-state quiescence involves multiple regulators, an exact nature of the regulators and underlying mechanisms are still incompletely understood. Here we showed that the signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of type I and II interferon receptor signaling, plays a cell-intrinsic role in regulating naïve CD8+ T cell responsiveness to tonic homeostatic cytokines. Thus, mice lacking STAT1 led to abnormalities in the composition and number of naïve and effector/memory phenotype among CD8+ T cells. The observed alterations were not due to dysregulation in thymic development but rather resulted from enhanced proliferative capacity of peripheral mature STAT1-deficient naïve CD8+ T cells in a cell-autonomous manner. In vitro analyses revealed that two key cytokines, IL-7 and type I interferon, serve as a major driver to induce abnormal proliferation of STAT1-deficient but not wild-type CD8+ T cells depending on a pathway that is sensitive to rapamycin, indicating a role of mTORC1 signaling. Based on these findings, we suggest that, under steady-state, naïve CD8+ T cells that are continuously exposed to homeostatic cytokines actively restrain their responsiveness to the “Goldilocks” levels – that is, not too strong to induce activation/proliferation and not too weak to lose a survival ability – presumably via blocking mTORC1 pathway, therefore maintaining a functional state of quiescence before encountering a cognate foreign antigen.