TCR/ITK signaling via mTOR tunes CD8+ T cell homeostatic proliferation, metabolism, and anti-tumor effector function

T cell homeostatic proliferation (HP) is regulated by T cell receptor (TCR) signals and homeostatic cytokines, and suggested to be proportional to TCR signal strength. However, we show here that ITK, a positive regulator of TCR signaling, negatively tunes CD8+ T cell HP, metabolism, and effector function. Under lymphopenic environments, Itk-/- CD8+ T cells exhibit significant increase in T cell-intrinsic HP, which requires mTOR activity and can be driven by T cell-T cell interaction. TCR signals through ITK tune IL-7-mediated CD8+ T cell metabolism and HP in a mTOR-dependent manner. The lack of ITK also resulted in enhanced effector cell fate programming, antigen sensitivity and anti-tumor immunity by HP cells. Thus, TCR signaling via ITK, is a negative tuner of CD8+ T cell homeostasis, metabolism and effector function, and may be a target for clinical benefit in cancer therapy.\n\nOne Sentence SummaryTCR signal strength had been long-thought to be proportional to T cell proliferation and effector function, here we demonstrate a counterintuitive role of the TCR signaling through ITK in negatively tuning proliferation under lymphopenic conditions via regulating mTOR activity, T cell metabolism, proliferation, and effector function.