The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Natalija Gerasimčik; Minghui He; Carin I M Dahlberg; Nikolai V Kuznetsov; Eva Severinson; Lisa S Westerberg

doi:10.3389/fimmu.2017.01264

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Front Immunol. 2017 Oct 6:8:1264. doi: 10.3389/fimmu.2017.01264. eCollection 2017.

Authors

Natalija Gerasimčik^{1

2}, Minghui He³, Carin I M Dahlberg^{3

4}, Nikolai V Kuznetsov³, Eva Severinson¹, Lisa S Westerberg³

Affiliations

¹ Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
² Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
³ Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
⁴ Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

Abstract

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^BRac2^-/- B cells). Rac1^BRac2^-/- mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1^BRac2^-/- B cells showed normal spreading response on antibody-coated layers, while both Rac2^-/- and Rac1^BRac2^-/- 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^BRac2^-/- mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1^BRac2^-/- mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1^BRac2^-/- 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.

Keywords: B cells; Ig class switching; Rac1; Rac2; humoral immune response.