Regulation of thymus-dependent and thymus-independent production of immunoglobulin G subclasses by Galpha12 and Galpha13

BACKGROUND A previous study from this laboratory showed that Galpha12 members participate in the production of inflammatory cytokines. In spite of the identification of B cell homeostasis responses regulated by Galpha13, the functional roles of Galpha12 members in the production of immunoglobulin (Ig) isotypes remained unknown. This study investigated whether Galpha12 members are involved in the Ig isotype antibody production with the purpose of establishing their functions in thymus-dependent and thymus-independent humoral responses. RESULTS Mice lacking Galpha12 and/or Galpha13 showed an impaired antigen-specific antibody production promoted by challenge(s) of ovalbumin or trinitrophenyl-lipopolysaccharide (TNP-LPS), used for thymus-dependent and thymus-independent stimuli, respectively. Homozygous knockout (KO) of Galpha12 or double heterozygous KO of Galpha12/Galpha13 significantly reduced the antigen-specific total IgG level after multiple ovalbumin immunizations with decreases in the production of IgG1, IgG2a and IgG2b subclasses, as compared to wild type control. In contrast, IgM production was not decreased. Moreover, mice deficient in Galpha12 or partially deficient in Galpha13 or Galpha12/Galpha13 showed significantly low production of IgG2b in response to TNP-LPS. In TNP-LPS-injected mice, IgG1 and IgG2a productions were unaffected by the G protein KOs. CONCLUSION Our results demonstrate that both Galpha12 and Galpha13 are essentially involved in thymus-dependent and independent production of IgG subclasses, implying that the G-proteins contribute to the process of antigen-specific IgG antibody production.