Upon their interaction with cognate antigen, T cells integrate different extracellular and intracellular signals involving basal and induced protein–protein interactions, as well as the binding of proteins to lipids, which can lead to either cell activation or inhibition. Here, we show that the selective T cell expression of CMIP, a new adapter protein, by targeted transgenesis drives T cells toward a naïve phenotype. We found that CMIP inhibits activation of the Src kinases Fyn and Lck after CD3/CD28 costimulation and the subsequent localization of Fyn and Lck to LRs. Video microscopy analysis showed that CMIP blocks the recruitment of LAT and the lipid raft marker cholera toxin B at the site of TCR engagement. Proteomic analysis identified several protein clusters differentially modulated by CMIP and, notably, Cofilin-1, which is inactivated in CMIP-expressing T cells. Moreover, transgenic T cells exhibited the downregulation of GM3 synthase, a key enzyme involved in the biosynthesis of gangliosides. These results suggest that CMIP negatively impacts proximal signaling and cytoskeletal rearrangement and defines a new mechanism for the negative regulation of T cells that could be a therapeutic target.
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We are grateful to Prof. Rose Zamoyska (Medical Research Council, London, United Kingdom) for providing us with the Tg(CD2-rtTA) CRza mouse model. This work was supported in part by a grant from the French Kidney Foundation. J.O., P.V., and K.S. were supported by grants from the Ministry of Research.
The authors declare no competing interests.
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Oniszczuk, J., Sendeyo, K., Chhuon, C. et al. CMIP is a negative regulator of T cell signaling. Cell Mol Immunol 17, 1026–1041 (2020). https://doi.org/10.1038/s41423-019-0266-5
- Transgenic mice
- T cells
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