FHL2 Is Essential for Spleen T Cell-Dependent B Cell Activation and Antibody Response

Four-and-a-half LIM domain protein 2 (FHL2) is an adaptor molecule regulating various cellular processes, including signal transduction, transcription, and cell survival. Although involved in inflammation and immune responses, its role in the germinal center reaction and B cell maturation remains unknown. We found that FHL2−/− mouse spleens displayed enlarged follicles with more B cells. When a T cell–dependent immune response was elicited using SRBC, FHL2−/− germinal center area was enhanced 2-fold compared with wild type (WT), concomitant with expanded dark zones. Nevertheless, the SRBC-induced rise in spleen IgG1 expression, and plasma IgG1 levels observed in WT were absent in FHL2−/− mice, and circulating plasma cells were also reduced in FHL2−/−. This could be explained by deficient upregulation of spleen activation-induced cytidine deaminase mRNA. Interestingly, FHL2−/− B cells successfully underwent class-switch recombination in vitro, and both activation-induced cytidine deaminase induction and IgG1 response to SRBC were equivalent in B cell–deficient μMT mice transplanted with WT or FHL2−/− bone marrow, suggesting that the defects observed in FHL2−/− mice were not B cell intrinsic. However, spleen lysates from FHL2−/− mice revealed a disturbed spleen microenvironment, with reduced CXCL12 and CXCL13 levels compared with WT. Our data suggest that spleen FHL2 expression is essential for a normal germinal center reaction and proper induction of class-switch recombination in response to a T cell–dependent Ag, leading to the emergence of Ab producing plasma cells. This could be due to the regulation of spleen cytokine production by FHL2.