Functional modulation of T follicular cells in vivo enhances antigen-specific humoral immunity

Abstract

Generation of high-affinity IgG is essential for defense against infections and cancer, is the intended consequence of many vaccines, but can cause autoimmune and inflammatory diseases when inappropriately directed against self (Wang et al., 2018, Ludwig et al., 2017, Chinen et al., 2010). The interplay and balance of T follicular helper cells (TFH) and T follicular regulatory cells (TFR) is critical for production of high-affinity IgG (Wing et al., 2018). Here, we empowered TFH cells and improve antigen-specific IgG responses with two interventions intended to transiently diminish TFR influence. First, adult mice were administered an antibiotic cocktail (ABX) for an extended period to deplete the immunoregulatory intestinal microbiota (Belkaid and Harrison, 2017, Thaiss et al., 2016, Rooks and Garrett, 2016, Honda and Littman, 2016, Perruzza et al., 2017, Teng et al., 2016, Block et al., 2016, Proietti et al., 2014, Slack et al., 2014). This treatment skewed T follicular cell ratios, with increased TFH and reduced TFR numbers. TNP-KLH immunization resulted in higher affinity TNP-specific IgG in ABX mice compared to controls. In a model of IgG-driven inflammatory nephritis, ABX mice had significantly worse nephritis accompanied by higher affinity antigen-specific IgG, and enriched TFH cells compared to controls. Second, we sought to functionally manipulate TFH and TFH cells, which both express the checkpoint inhibitory molecule, PD-1 (Sage et al., 2013), by administration of -PD-1 during immunization. This intervention enhanced the affinity of antigen-specific IgG and increased in TFH following TNP-KLH immunization and nephritis induction. These results suggest that altering TFH and TFR ratio during immunization is an appealing strategy to qualitatively improve IgG responses.