Deciphering the role of extrafollicular-derived IgM on germinal center memory and long-lived plasma cell responses to Influenza virus infection 2257479

Abstract

Abstract Introduction Most if not all the IgM secreted early after Influenza virus infection by B-1 and B-2 cells is derived from antibody-secreting cells (ASCs) developing in rapidly forming extrafollicular (EF) B cell responses. We previously demonstrated that the lack of the early-derived IgM significantly reduces the later-induced IgG response to influenza A virus (IAV) infection. The mechanisms underlying this effect on IgG remain to be fully explored. Here we hypothesize that EF-derived IgM affects antigen retention and stimulation of germinal center (GC) B cells, promoting stronger selection for memory and plasma cell differentiation in GCs. Methods Flow cytometry, ELISPOT, ELISA. Results To investigate the impact of reduced EF response output on GC functionality, we infected secreted IgM knockout (s-IgM KO) mice with IAV and analyzed the draining mediastinal lymph nodes (medLN) for alterations in GC B cell frequencies at day 14 post-infection. Our initial studies demonstrate significant reductions in both frequency and total numbers of GC B cells in s-IgM KO mice compared to wild-type (WT) controls. Moreover, we found that s-IgM KO mice harbored significantly fewer CD80+,CD73+, Influenza hemagglutinin (HA)-specific memory B cells at 30 days post infection (p.i) and decreased HA+ plasma cells in the bone marrow compared to WT mice at 45 days p.i. Antigen-specific serum and bone marrow antibody levels were assessed by ELISA and ELISPOT, and female s-IgMKO mice showed a reduction in IgG levels compared to WT after 45 days p.i. Conclusion Collectively, this data suggests that early EF-derived IgM responses are critical to support maximal GC outputs. Understanding these mechanisms may provide valuable insights for optimizing vaccine strategies against IAV infections. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)