Minguet, SusanaKläsener, KathrinSchaffer, Anna-MariaFiala, Gina JOsteso-Ibánez, TeresaRaute, KatrinNavarro-Lérida, InmaculadaHartl, Frederike ASeidl, MaximilianReth, MichaelDel Pozo, Miguel A2026-01-142026-01-142017-10Nat Immunol. 2017 Oct;18(10):1150-1159.https://hdl.handle.net/20.500.12105/27143Caveolin-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.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).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International2880581118101150-1159Nature mmunologyopen access