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

Hasiuk, M.; Negraschus, A.; Seyres, D.; Marone, R.; Jankevicius, G.; Siewert, L.; Schultheiss, C.; Blazquez, A. M.; Binder, M.; Proebstel, A.-K.; Hiller, S.; Heissmeyer, V.; Jeker, L. T.

doi:10.1101/2025.07.01.662281

bioRxiv · 10.1101/2025.07.01.662281

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

Hasiuk, M.·Negraschus, A.·Seyres, D.·Marone, R.·Jankevicius, G.·Siewert, L.·Schultheiss, C.·Blazquez, A. M.·Binder, M.·Proebstel, A.-K.·Hiller, S.·Heissmeyer, V.·Jeker, L. T.

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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-2R{gamma}) in a multi-protein complex. Tmem127 reduces IL-7 receptor surface expression to restrict homeostatic proliferation, thereby controlling naive 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.

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Hasiuk, M., Negraschus, A., Seyres, D., Marone, R., Jankevicius, G., Siewert, L., Schultheiss, C., Blazquez, A. M., Binder, M., Proebstel, A.-K., Hiller, S., Heissmeyer, V., Jeker, L. T.. 2025-07-04. Tmem127-mediated immune receptor degradation regulates T cell homeostasis through the common gamma chain. https://doi.org/10.1101/2025.07.01.662281

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