Abstract

Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-μ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell–induced autoimmunity by means of its role in plasma-membrane organization.

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Acknowledgements

We thank the BIOSS toolbox for reagents; M.C. Guadamillas and A. Cerezo for the generation of the B6.Cav1Y14F/Y14F mice; E. Hobeika (Max Planck Institute of Immunology and Epigenetics) for Cd79a−/− mice; H. Jumaa (Max Planck Institute of Immunology and Epigenetics) for 3-83Igi mice; C. Johner, U. Stauffer, N. Joswig, and K. Fehrenbach for experimental help; Y. Kulathu, M. Swamy M. Rizzi, K. Schachtrup and Y.R. Carrasco for critical reading of the manuscript; and W. Schamel for intellectual input and scientific discussions. Supported by the German Research Foundation (DFG) (SFB1160 IMPATH P5 to S.M., supporting F.A.H. and A.-M.S.; MI1942/2-1 to S.M., supporting G.J.F.; the Spemann Graduate School (Excellence Initiative GSC-4 to K.R.); the BIOSS Centre for Biological Signalling Studies (EXC294 to S.M. and M.R.); TRR130-P02 to M.R.; and SFB746-P07 to M.R), the European Research Council (32297 to M.R.), the Spanish Ministry of Economy and Competitiveness (SAF2008-02100 (support for S.M. in 2008); SAF2011-25047, CSD2009-00016 and SAF2014-51876-R to M.A.D.P.; and support for CNIC), the Worldwide Cancer Research Foundation (15-0404 to M.A.D.P.), the Ramón y Cajal Program from the MINECO (2009-2011 to S.M.), Asociación Española Contra el Cáncer (I.N.-L.), the Pro-CNIC Foundation (support for CNIC) and Severo Ochoa Center of Excellence (SEV-2015-0505 for CNIC).

Author information

Affiliations

  1. Department of Immunology, Institute for Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany.

    • Susana Minguet
    • , Kathrin Kläsener
    • , Anna-Maria Schaffer
    • , Gina J Fiala
    • , Katrin Raute
    • , Frederike A Hartl
    •  & Michael Reth
  2. Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany.

    • Susana Minguet
    • , Kathrin Kläsener
    • , Gina J Fiala
    • , Katrin Raute
    • , Frederike A Hartl
    •  & Michael Reth
  3. Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

    • Susana Minguet
    • , Anna-Maria Schaffer
    •  & Maximilian Seidl
  4. Mechanoadaptation & Caveolae Biology Lab, Cell Biology & Physiology Program; Cell & Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

    • Susana Minguet
    • , Teresa Osteso-Ibánez
    • , Inmaculada Navarro-Lérida
    •  & Miguel A Del Pozo
  5. Max Planck Institute of Immunology and Epigenetics, Freiburg, Germany.

    • Kathrin Kläsener
    •  & Michael Reth
  6. Spemann Graduate School for Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.

    • Katrin Raute
  7. Institute for Surgical Pathology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Maximilian Seidl

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Contributions

S.M. designed this study, performed experiments and wrote the manuscript with input from all authors; K.K. and A.-M.S. performed the PLA experiments; G.J.F. and F.A.H. performed ex vivo stimulation; T.O.-I. raised the mice and performed experiments; K.R. and M.S. performed kidney analysis; I.N.-L. performed DRM experiments; M.R. provided intellectual input and conceptual and scientific advice; M.A.D.P. provided B6.Cav1Y14F/Y14F mice, Cav1 expertise to the conception of the project and intellectual input and conceptual and scientific advice; and all authors critically read the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Susana Minguet.

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https://doi.org/10.1038/ni.3813

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