Journal Articles Journal of Experimental Medicine Year : 2025

A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo

Lichen Zhang
Liaoxun Lu
Marielle Mello
Frédéric Fiore
Yinming Liang

Abstract

Naive T cell activation requires both TCR and CD28 signals. The CARMIL2 cytosolic protein enables CD28-dependent activation of the NF-κB transcription factor via its ability to link CD28 to the CARD11 adaptor protein. Here, we developed mice expressing a mutation named Carmil2QE and mimicking a mutation found in human T cell malignancies. Naive T cells from Carmil2QE mice contained preformed CARMIL2QE-CARD11 complexes in numbers comparable to those assembling in wild-type T cells after CD28 engagement. Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent. In turn, tumor-specific T cells expressing Carmil2QE do not require CD28 engagement and thereby escape to both PD-1 and CTLA-4 inhibition. In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor–specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.

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hal-05390008 , version 1 (12-12-2025)

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Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, et al.. A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo. Journal of Experimental Medicine, 2025, 222 (8), pp.e20250339. ⟨10.1084/jem.20250339⟩. ⟨hal-05390008⟩
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