Autor: |
Gerasimčik N; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.; Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden., He M; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Dahlberg CIM; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Kuznetsov NV; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Severinson E; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden., Westerberg LS; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. |
Abstrakt: |
The Rho GTPases Cdc42, Rac1, and Rac2 coordinate receptor signaling to cell adhesion, migration, and proliferation. Deletion of Rac1 and Rac2 early during B cell development leads to failure in B cell entry into the splenic white pulp. Here, we sought to understand the role of Rac1 and Rac2 in B cell functionality and during the humoral antibody response. To circumvent the migratory deficiency of B cells lacking both Rac1 and Rac2, we took the approach to inducibly delete Rac1 in Rac2 -/- B cells in the spleen (Rac1 B Rac2 -/- B cells). Rac1 B Rac2 -/- mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1 B Rac2 -/- B cells showed normal spreading response on antibody-coated layers, while both Rac2 -/- and Rac1 B Rac2 -/- B cells had reduced homotypic adhesion and decreased proliferative response when compared to wild-type B cells. Upon challenge with the T-cell-independent antigen TNP-conjugated lipopolysaccharide, Rac1 B Rac2 -/- mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1 B Rac2 -/- mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1 B Rac2 -/- B cells had elevated germline γ2b transcripts leading to increased Ig class switching to IgG2b. Our data suggest that Rac1 and Rac2 serve an important role in regulation of the B cell humoral immune response and in suppressing Ig class switching to IgG2b. |