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

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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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-05-22
DOI
https://doi.org/10.1084/jem.20250339
Citations
2
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
1.59

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article

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

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2 citations
The Journal of Experimental Medicine
Immune Cell Function and Interaction
1.59
article

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

Yinming Liang, Guillaume Voisinne, Romain Roncagalli, Anne Gonzalez de Peredo, Marie Malissen, Fanghui Zhang, Frédéric Di Fiore, Liaoxun Lu, Bernard Malissen, Daiki Mori, Odile Burlet‐Schiltz, Valentin Mellado, Marielle Mello, Léna Gelard, Javier Celis‐Gutierrez, Lichen Zhang, Carine Vilarnau Wolek, Sophie Panigot
article en
2 citations

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.

The Journal of Experimental MedicineVol. 222(8)
Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Aix-Marseille Université (FR), Institut de Pharmacologie et de Biologie Structurale (FR), Centre d’Immunologie de Marseille-Luminy (FR), Centre d'Immunophénomique, Henan Medical University (CN)
Aix-Marseille Université, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, PHENOMIN, National Outstanding Youth Science Fund Project of National Natural Science Foundation of China, European Research Council, MSDAVENIR
Good health and well-being
Openalex Percentile: Top 17%
Immune Cell Function and Interaction
1.59
DOIOpen Access PDFOpenAlex
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