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

Publié dans: J Exp Med 2025 Aug; 222(8):

Auteurs: Zhang F, Celis-Gutierrez J, Zhang L, Mellado V, Gelard L, Panigot S, Mori D, Lu L, Voisinne G, Vilarnau Wolek C, Mello M, Burlet-Schiltz O, Gonzalez de Peredo A, Fiore F, Roncagalli R, Liang Y, Malissen M, Malissen B

Résumé

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.

Lien vers Pubmed [PMID] – 40402149

Lien vers le DOI – 10.1084/jem.20250339