Article | Published:

Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation

Nature Immunology volume 15, pages 10461054 (2014) | Download Citation

Abstract

Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.

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Acknowledgements

We thank S. Ryeom (University of Pennsylvania) for the RCAN1 expression vector; G. Nolan (Stanford University) for Phoenix Ecotropic cells; S. Kaushik for help in the preparation of lysosomal fractions; and S. Bandyopadhyay for assistance in chromatin immunoprecipitation experiments. Supported by the US National Institutes of Health (AG031782), the Glenn Foundation (F.M. and A.M.C.) and the Einstein Nathan Shock Center in Basic Research in Aging (AG038072, for the use of specific research cores).

Author information

Author notes

    • Enric Mocholi
    • , Yair Botbol
    •  & Ignacio Guerrero-Ros

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Rut Valdor
    • , Enric Mocholi
    • , Yair Botbol
    • , Ignacio Guerrero-Ros
    •  & Fernando Macian
  2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Dinesh Chandra
    •  & Claudia Gravekamp
  3. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Hiroshi Koga
    •  & Ana Maria Cuervo
  4. Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Claudia Gravekamp
    • , Ana Maria Cuervo
    •  & Fernando Macian

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Contributions

R.V. designed and did experiments, analyzed data and wrote manuscript; E.M., Y.B., I.G.-R., D.C. and H.K. did experiments and contributed to data interpretation; C.G. designed experiments and interpreted data; A.M.C. designed project and interpreted data; and F.M. conceived of and directed project, interpreted data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fernando Macian.

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https://doi.org/10.1038/ni.3003

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