Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CMIP is a negative regulator of T cell signaling

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Brubaker, S. W., Bonham, K. S., Zanoni, I. & Kagan, J. C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 33, 257–290 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chakraborty, A. K. & Weiss, A. Insights into the initiation of TCR signaling. Nat. Immunol. 15, 798–807 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Viola, A. & Gupta, N. Tether and trap: regulation of membrane-raft dynamics by actin-binding proteins. Nat. Rev. Immunol. 7, 889–896 (2007).

    CAS  PubMed  Google Scholar 

  4. Brownlie, R. J. & Zamoyska, R. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13, 257–269 (2013).

    CAS  PubMed  Google Scholar 

  5. Sahali, D. et al. A novel approach to investigation of the pathogenesis of active minimal- change nephrotic syndrome using subtracted cDNA library screening. J. Am. Soc. Nephrol. 13, 1238–1247 (2002).

    CAS  PubMed  Google Scholar 

  6. Boumediene, A. et al. NEPHRUTIX: a randomized, double-blind, placebo vs Rituximab-controlled trial assessing T-cell subset changes in Minimal Change Nephrotic Syndrome. J. Autoimmun. 88, 91–102 (2018).

    CAS  PubMed  Google Scholar 

  7. Sendeyo, K. et al. Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy. Kidney Int. 83, 414–425 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bouachi, K. et al. Expression of CMIP in podocytes is restricted to specific classes of lupus nephritis. PLoS ONE 13, e0207066 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. Audard, V. et al. Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes. Blood 115, 3756–3762 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouatou, Y. et al. Nephrotic syndrome in small cell lung cancer and induction of C-Mip in podocytes. Am. J. Kidney Dis. 2017;69:477–480.

  11. Kamal, M. et al. C-mip interacts physically with RelA and inhibits nuclear factor kappa B activity. Mol. Immunol. 46, 991–998 (2009).

    CAS  PubMed  Google Scholar 

  12. Kamal, M. et al. C-mip interacts with the p85 subunit of PI3 kinase and exerts a dual effect on ERK signaling via the recruitment of Dip1 and DAP kinase. FEBS Lett. 584, 500–506 (2010).

    CAS  PubMed  Google Scholar 

  13. Grimbert, P. et al. The Filamin-A is a partner of Tc-mip, a new adapter protein involved in c-maf-dependent Th2 signaling pathway. Mol. Immunol. 40, 1257–1261 (2004).

    CAS  PubMed  Google Scholar 

  14. Izzedine, H. et al. Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy. Kidney Int. 85, 457–470 (2014).

    CAS  PubMed  Google Scholar 

  15. Ory, V. et al. c-mip down-regulates NF-kappaB activity and promotes apoptosis in podocytes. Am. J. Pathol. 180, 2284–2292 (2012).

    CAS  PubMed  Google Scholar 

  16. Izzedine, H. et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine 93, 333–339 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Moktefi, A. et al. Repression of CMIP transcription by WT1 is relevant to podocyte health. Kidney Int. 90, 1298–1311 (2016).

    CAS  PubMed  Google Scholar 

  18. Nakao, A. et al. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J. Exp. Med. 192, 151–158 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ballarin-Gonzalez, B. et al. Protection and systemic translocation of siRNA following oral administration of Chitosan/siRNA nanoparticles. Mol. Ther. Nucleic Acids 2, e76 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Gao, S. et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Mol. Ther. 17, 1225–1233 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Malissen, B. & Bongrand, P. Early T cell activation: integrating biochemical, structural, and biophysical cues. Annu Rev. Immunol. 33, 539–561 (2015).

    CAS  PubMed  Google Scholar 

  22. Zeng, P., Xu, Y., Zeng, C., Ren, H. & Peng, M. Chitosan-modified poly(D,L-lactide-co-glycolide) nanospheres for plasmid DNA delivery and HBV gene-silencing. Int J. Pharm. 415, 259–266 (2011).

    CAS  PubMed  Google Scholar 

  23. Eibert, S. M. et al. Cofilin peptide homologs interfere with immunological synapse formation and T cell activation. Proc. Natl Acad. Sci. USA 101, 1957–1962 (2004).

    CAS  PubMed  Google Scholar 

  24. Yu, L. et al. cMaf inducing protein inhibits cofilin1 activity and alters podocyte cytoskeleton organization. Mol. Med. Rep. 16, 4955–4963 (2017).

    CAS  PubMed  Google Scholar 

  25. Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

    CAS  PubMed  Google Scholar 

  26. Xie, J. et al. Phosphotyrosine-dependent interaction between the kinases PKCtheta and Zap70 promotes proximal TCR signaling. Sci. Signal. 2019;12:eaar3349.

  27. Zanin-Zhorov, A. et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328, 372–376 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ghosh, P., Tan, T. H., Rice, N. R., Sica, A. & Young, H. A. The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. Proc. Natl Acad. Sci. USA 90, 1696–1700 (1993).

    CAS  PubMed  Google Scholar 

  29. Bomsztyk, K. et al. Evidence that interleukin-1 and phorbol esters activate NF-kappa B by different pathways: role of protein kinase C. Cell Regul. 2, 329–335 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zamoyska, R. et al. The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation. Immunol. Rev. 191, 107–118 (2003).

    CAS  PubMed  Google Scholar 

  31. Tuosto, L. et al. Organization of plasma membrane functional rafts upon T cell activation. Eur. J. Immunol. 31, 345–349 (2001).

    CAS  PubMed  Google Scholar 

  32. Garofalo, T. et al. Association of GM3 with Zap-70 induced by T cell activation in plasma membrane microdomains: GM3 as a marker of microdomains in human lymphocytes. J. Biol. Chem. 277, 11233–11238 (2002).

    CAS  PubMed  Google Scholar 

  33. Nagafuku, M. et al. CD4 and CD8 T cells require different membrane gangliosides for activation. Proc. Natl Acad. Sci. USA 109, E336–E342 (2012).

    CAS  PubMed  Google Scholar 

  34. Dykstra, M., Cherukuri, A., Sohn, H. W., Tzeng, S. J. & Pierce, S. K. Location is everything: lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21, 457–481 (2003).

    CAS  PubMed  Google Scholar 

  35. Davis, D. M. & Dustin, M. L. What is the importance of the immunological synapse? Trends Immunol. 25, 323–327 (2004).

    CAS  PubMed  Google Scholar 

  36. Zumerle, S., Molon, B. & Viola, A. Membrane rafts in T cell activation: a spotlight on CD28 costimulation. Front. Immunol. 8, 1467 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Ballek, O. et al. TCR triggering induces the formation of Lck-RACK1-Actinin-1 multiprotein network affecting Lck redistribution. Front. Immunol. 7, 449 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Zhang, S. Y. et al. c-mip impairs podocyte proximal signaling and induces heavy proteinuria. Sci. Signal. 3, ra39 (2010).

    PubMed  PubMed Central  Google Scholar 

  39. Varshney, P., Yadav, V. & Saini, N. Lipid rafts in immune signalling: current progress and future perspective. Immunology 149, 13–24 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sahali, D. et al. Immunopathogenesis of idiopathic nephrotic syndrome with relapse. Semin. Immunopathol. 36, 421–429 (2014).

    PubMed  PubMed Central  Google Scholar 

  41. Kassu, A. et al. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185, 3007–3018 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hodi, F. S. et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl Acad. Sci. USA 100, 4712–4717 (2003).

    CAS  PubMed  Google Scholar 

  43. Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).

    CAS  PubMed  Google Scholar 

  44. Macdonald, J. L. & Pike, L. J. A simplified method for the preparation of detergent-free lipid rafts. J. Lipid Res. 46, 1061–1067 (2005).

    CAS  PubMed  Google Scholar 

  45. Bourderioux, M. et al. A new workflow for proteomic analysis of urinary exosomes and assessment in cystinuria patients. J. Proteome Res. 14, 567–577 (2015).

    CAS  PubMed  Google Scholar 

  46. Xia, J., Mandal, R., Sinelnikov, I. V., Broadhurst, D. & Wishart, D. S. MetaboAnalyst 2.0–a comprehensive server for metabolomic data analysis. Nucleic Acids Res. 40(Web Server issue), W127–W133 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, F. et al. MPINet: metabolite pathway identification via coupling of global metabolite network structure and metabolomic profile. BioMed. Res. Int. 2014;2014:325697.

  48. Cavill, R. et al. Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells. PLoS Comput. Biol. 7, e1001113 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Julie Oniszczuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kelhia Sendeyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cerina Chhuon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Berkan Savas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Etienne Cogné
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pauline Vachin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carole Henique
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ida Chiara Guerrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Astarita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vincent Frontera
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Andre Pawlak
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vincent Audard
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dil Sahali
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mario Ollero
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Dil Sahali.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0266-5

Keywords

This article is cited by

Search

Advanced search

Quick links