Impaired Th17 immunity in recurrent C. difficile infection is ameliorated by fecal microbial transplantation

Background & AimsClostridioides difficile is a leading cause of infectious diarrhea and an urgent antimicrobial resistant threat. Symptoms are caused by its toxins, TcdA and TcdB, with many patients developing recurrent C. difficile infection (CDI), requiring fecal microbiota transplant (FMT). Antibody levels have not been useful in predicting patient outcomes, which is an unmet need. We aimed to characterize T cell-mediated immunity to C. difficile toxins and assess how these responses were affected by FMT. MethodsWe obtained blood samples from patients with newly acquired CDI, recurrent CDI (with a subset receiving FMT), inflammatory bowel disease with no history of CDI, and healthy individuals (controls). Toxin-specific CD4+ T cell responses were analysed using a whole blood flow cytometry antigen-induced marker assay. Serum antibodies were measured by ELISA. Tetramer guided mapping was used to identify HLA-II-restricted TcdB epitopes and DNA was extracted from TcdB-specific CD4+ T cells for TCR repertoire analysis by Sanger sequencing. ResultsCD4+ T cell responses to C. difficile toxins were functionally diverse. Compared to controls, individuals with CDI, or inflammatory bowel disease had significantly higher frequencies of TcdB-specific CD4+ T cells. Subjects with recurrent CDI had reduced proportions of TcdB-specific CD4+ Th17 cells, FMT reversed this deficit and increased toxin-specific antibody production. ConclusionsThese data suggest that effective T cell immunity to C. difficile requires the development of Th17 cells. In addition, they show that an unknown aspect of the therapeutic effect of FMT may be enhanced T and B cell-mediated immunity to TcdB. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/20114876v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@cc5a23org.highwire.dtl.DTLVardef@31e074org.highwire.dtl.DTLVardef@86fd85org.highwire.dtl.DTLVardef@6e3771_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG