IL-12 Blocks Tfh Cell Differentiation during Salmonella Infection, thereby Contributing to Germinal Center Suppression

Abstract

Germinal centers (GC) are crucial for the formation of long-lived humoral immunity. Many pathogens suppress GC, including Salmonella enterica serovar Typhimurium (STm), but the mechanisms driving suppression remain unknown. We report that neither plasmablasts nor STm-specific B cells are required for GC suppression in mice. Rather, we identify that interleukin-12 (IL-12), but not interferon-γ (IFN-γ), directly suppresses T follicular helper (Tfh) cell differentiation of T cells intrinsically. Administering recombinant IL-12 during nitrophenyl-Chicken Gamma Globulin (NP-CGG) immunization also suppresses Tfh cell differentiation and GC B cells, indicating that IL-12 is sufficient to suppress Tfh cell differentiation independent of STm infection. Recombinant IL-12 induces high levels of T-bet, and T-bet is necessary for Tfh cell suppression. Therefore, IL-12 induced during STm infection in mice contributes to GC suppression via suppression of Tfh cell differentiation. More broadly, these data suggest that IL-12 can tailor the proportions of humoral (Tfh cell) and cellular (T helper type 1 [Th1] cell) immunity to the infection, with implications for IL-12 targeting therapies in autoimmunity and vaccination.

Keywords: IL-12; Salmonella; T follicular helper; T-bet; germinal center suppression; plasma cells.