EFhd2/ Swiprosin-1 regulates the cytoskeleton of B lymphocytes and impacts germinal center reaction

Abstract

Abstract The germinal center (GC) reaction is a decisive checkpoint for efficient humoral immunity. Most GC associated processes, e.g. cell migration and cell adhesion, are strongly dependent on cytoskeletal dynamics and B cell receptor (BCR) signaling. However, the molecular connection between downstream BCR molecules and cytoskeletal proteins is not yet fully elucidated. The adaptor protein EFhd2/ Swiprosin-1 co-localizes with the BCR at the plasma membrane. It controls F-Actin bundling as well as Actin remodeling through Cofilin activity and is involved in spreading, lamellipodia formation and migration in non-lymphoid cells. We showed that constitutively EFhd2 deficient mice display enhanced GC responses upon challenge with the helminth Nippostrongylus brasiliensis in a B cell intrinsic manner in mixed bone marrow chimeras. Moreover, B cell specific deletion of EFhd2 leads to enhanced GC B cell numbers already in steady state. We therefore hypothesize that EFhd2 controls the GC reaction by regulating cytoskeletal processes. In vitro transwell migration assays and in vivo studies using two-photon microscopy revealed decreased directed chemotaxis but increased random chemokinesis of EFhd2−/− B cells. Moreover, activated B cells spread faster in the absence of EFhd2 on anti-BCR antibodies which correlates with accelerated Cofilin activity. Finally, also BCR capping was increased in activated EFhd2 deficient B cells. Taken together, we suggest that EFhd2 controls Actin dynamics through Cofilin in B cells, thereby, controlling chemotaxis of B cells and BCR mediated B cell spreading. Hence, EFhd2 links proper coordination of the B cell cytoskeleton with the GC checkpoint and impacts TH2 response.