Tmem127-mediated immune receptor degradation regulates T cell homeostasis through the common gamma chain

Abstract Maintenance of T cell population size, which is important for immune homeostasis, is controlled by interleukin-7 (IL-7) and low-affinity TCR/MHC interactions that provide limited survival cues. Using arrayed CRISPR screening of miR-17∼92 targets, Bio-ID proximity labeling and proteomics we identified Tmem127 as an essential regulator of the T cell surface proteome. We validated interaction with the common gamma chain (IL-2Rγ) in a multi-protein complex. Tmem127 reduces IL-7 receptor surface expression to restrict homeostatic proliferation, thereby controlling naïve and central memory T cell population sizes. Tmem127 germline knockout (KO) mice display splenomegaly, accelerated experimental autoimmune encephalomyelitis and Tmem127-deficient bone marrow displays a competitive advantage over wildtype cells. Thus, we identified Tmem127 as an important regulator of the common gamma chain and immune homeostasis. Competing Interest Statement LTJ: co-founder, holding equity of Cimeio Therapeutics AG (Cimeio). Cimeio board member. Sponsored research agreement with Cimeio. Inventor on granted patents and patent applications related to immune cell engineering. Received speaker fees from Novartis. Paid consultant for Kyowa Kirin. No competing interests directly affecting this study. All other authors declare that they have no competing interests.