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Peyer’s patch TH17 cells are dispensable for gut IgA responses to oral immunization

T helper 17 (TH17) cells located at the Peyer’s patch (PP) inductive site and at the lamina propria effector site of the intestinal immune system are responsive to both pathogenic and commensal bacteria. Their plasticity to convert into follicular helper T (TFH) cells has been proposed to be central to gut immunoglobulin A (IgA) responses. Here, we used an IL-17A fate reporter mouse and an MHC-II tetramer to analyze antigen-specific CD4+ T cell subsets and isolate them for single-cell RNA sequencing after oral immunization with cholera toxin and ovalbumin. We found a TFH-dominated response with only rare antigen-specific TH17 cells (<8%) in the PP. A clonotypic analysis provided little support that clonotypes were shared between TFH and TH17 cells, arguing against TH17 plasticity as a major contributor to TFH differentiation. Two mouse models of TH17 deficiency confirmed that gut IgA responses to oral immunization do not require TH17 cells, with CD4CreRorcfl/fl mice exhibiting normal germinal centers in PP and unperturbed total IgA production in the intestine. Description TH17-deficient conditional knockout mice lacking Rorc in T cells exhibit unperturbed gut IgA responses to oral immunization. Plasticity-independent TFH cells At mucosal inductive sites like small intestinal Peyer’s patches (PPs), CD4+ follicular helper T (TFH) cells are critical for gut immunoglobulin A (IgA) responses against T cell–dependent antigens. Whether these cells arise from T helper 17 (TH17) cells that subsequently transform into TFH cells in PP has been a topic of debate. Using oral immunization of mice with cholera toxin and ovalbumin as model antigens and single-cell RNA sequencing analysis of tetramer+ PP T cells, Gribonika et al. found that antigen-specific TFH cells in PP develop in the complete absence of IL-17A–producing T cells, suggesting that TH17 cells are dispensable for gut IgA responses. Strains of Rorc knockout mice that lack TH17 cells exhibited unperturbed gut IgA responses. These findings provide valuable insights into designing more effective oral vaccines.