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Updated: May 23, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo
Fanghui Zhang1,2, Javier Celis-Gutierrez1, Lichen Zhang2
1Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, Institut national de la santé et de la recherche médicale (INSERM), Centre national de la recherche scientifique (CNRS) , Marseille, France.
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.
Insights
Researchers discovered that CARMIL2-CARD11 signaling bypasses CD28 dependency for T cell activation. This finding enables potent anti-tumor responses, even when CD28 is absent or inhibited by immune checkpoints.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Naive T cell activation critically depends on T cell receptor (TCR) and CD28 co-stimulatory signals.
- The CARMIL2 protein links CD28 to the CARD11 adaptor, facilitating CD28-dependent NF-κB activation.
- Mutations in CARMIL2 are implicated in human T cell malignancies.
Purpose of the Study:
- To investigate the role of CARMIL2 in T cell activation.
- To develop a mouse model mimicking human T cell malignancy mutations in CARMIL2.
- To explore the potential of CARMIL2-CARD11 signaling in overcoming CD28 dependency for anti-tumor immunity.
Main Methods:
- Generation of Carmil2QE mutant mice, mimicking human T cell malignancy mutations.
- Analysis of CARMIL2-CARD11 complex formation in wild-type and mutant T cells.
- Assessment of T cell functions in CD28-deficient and Carmil2QE mutant mice.
- Evaluation of tumor-specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.
Main Results:
- Carmil2QE mutant mice exhibit preformed CARMIL2QE-CARD11 complexes, similar to wild-type cells upon CD28 engagement.
- These preformed complexes induce CD28-like functions in a CD28-independent manner, even in CD28-deficient mice.
- Tumor-specific T cells expressing Carmil2QE bypass the need for CD28 engagement.
- Carmil2QE-expressing T cells evade inhibition by PD-1 and CTLA-4, crucial immune checkpoint inhibitors.
Conclusions:
- CARMIL2-CARD11 signaling plays a central role in CD28-mediated T cell activation.
- Exploiting CARMIL2-CARD11 signaling can induce potent T cell responses independently of CD28.
- This strategy offers a promising approach for enhancing anti-tumor immunity, overcoming resistance to immune checkpoint inhibitors.
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