Role of innate signaling pathways in the regulation of antiviral IgG2c responses (108.9)

Abstract

Abstract Long-term antibody responses provide protection from re-infection and recrudescence of persistent viruses. IgG2a/c is a predominant immunoglobulin isotype in most virus infections. Using a polyomavirus (PyV) mouse model, our lab has shown that MyD88 KO mice generate low levels of virus-specific IgG after the acute phase of infection, have reduced numbers of long-lived plasma cells and make very low levels of IgG2c, but normal levels of IgG1. Investigating the pathways upstream and downstream of MyD88, here we show that in response to PyV infection (i) Unc93B1 mutant mice, which are triple deficient in TLR3, 7 and 9 have diminished IgG2c, but normal IgG1 responses; (ii) TLR9 KO and TLR7 KO mice do not have greatly altered IgG isotype responses as observed in MyD88 KO mice or the Unc93B1 mutant mice, suggesting that these receptors play a redundant role; and (iii) mice lacking IRF5, a transcriptional regulator downstream of MyD88, have greatly diminished IgG2c and normal IgG1 responses, similar to MyD88 KO mice. The isotype switching defect observed in IRF5 KO mice is B cell intrinsic, as transfer of IRF5 KO B cells and WT T cells into RAG KO mice results in diminished antiviral IgG2c secretion compared to mice reconstituted with B6 B and T cells. Therefore, our studies suggest that TLR7/9-MyD88-IRF5 pathways in B cells play an essential role in the generation of IgG2a/c responses to virus infection.