Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance

• Published in: Nature immunology Vol. 18; no. 10; pp. 1150 - 1159
• Main Authors: Minguet, Susana, Kläsener, Kathrin, Schaffer, Anna-Maria, Fiala, Gina J, Osteso-Ibánez, Teresa, Raute, Katrin, Navarro-Lérida, Inmaculada, Hartl, Frederike A, Seidl, Maximilian, Reth, Michael, Del Pozo, Miguel A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2017; Nature Publishing Group
• Subjects: 631/250/2152/569; 631/250/38; 64/110; 96; 96/100; 96/106; 96/109; 96/31; 96/63; 96/95; Animals; Antigens; Autoimmunity; Autoimmunity - genetics; Autoimmunity - immunology; B cells; B-cell receptor; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Caveolin; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin-1; Caveolins; Cell receptors; Gene Expression; Genetic aspects; Glycolipids; Health aspects; Immune response regulation; Immune Tolerance - genetics; Immunoglobulin D; Immunoglobulin D - immunology; Immunoglobulin D - metabolism; Immunoglobulin M; Immunoglobulin M - immunology; Immunoglobulin M - metabolism; Immunoglobulins; Immunological tolerance; Immunology; Infectious Diseases; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocyte receptors; Lymphocytes B; Mice; Mice, Knockout; Mice, Transgenic; Phosphorylation; Protein Binding; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.3813

Immature B cells are subject to tolerance mechanisms that prevent the expression of self-reactive BCRs. Minguet and colleagues identify the membrane protein caveolin-1 as a regulator of BCR spatial organization and signaling that enforces B cell tolerance. 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.