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CMIP is a negative regulator of T cell signaling

Cellular & Molecular Immunology volume 17, pages 1026–1041 (2020)Cite this article

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Abstract

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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Acknowledgements

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.

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  1. These authors contributed equally: Julie Oniszczuk, Kelhia Sendeyo

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 955, Equipe 21, F-94010, Créteil, France

    Julie Oniszczuk, Kelhia Sendeyo, Berkan Savas, Etienne Cogné, Pauline Vachin, Carole Henique, Vincent Frontera, Andre Pawlak, Vincent Audard, Dil Sahali & Mario Ollero

  2. Faculté de Médecine, Université Paris Est, UMRS 955, Equipe 21, F-94010, Créteil, France

    Julie Oniszczuk, Kelhia Sendeyo, Berkan Savas, Etienne Cogné, Pauline Vachin, Carole Henique, Vincent Frontera, Andre Pawlak, Vincent Audard, Dil Sahali & Mario Ollero

  3. Proteomic Platform Necker, PPN-3P5, Structure Fédérative de Recherche SFR Necker US24, 75015, Paris, France

    Cerina Chhuon & Ida Chiara Guerrera

  4. Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA

    Giuseppe Astarita

  5. AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, F-94010, Créteil, France

    Vincent Audard & Dil Sahali

  6. Institut Francilien De Recherche En Néphrologie Et Transplantation, F-94010, Créteil, France

    Vincent Audard & Dil Sahali

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  1. Julie Oniszczuk
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Contributions

J.O., K.S., C.C., P.V., B.S., E.C., C.H., V.F., A.P., G.A. and I.C.G. performed the experiments. M.O., V.A. and D.S. wrote the paper. D.S. and M.O. supervised the project. All authors discussed the results and participated in writing the paper.

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Correspondence to Dil Sahali.

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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

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