Clostridioides difficile toxin B inhibits antigen-specific adaptive immune responses through glucosyltransferase-dependent activity 3906

Abstract Description Clostridioides difficile colonizes the gastrointestinal tract and secretes two major virulence factors: toxin A (TcdA) and toxin B (TcdB). Protective immunity to C. difficile infection is limited as patients are susceptible to severe recurrent infections, often by the same strain as the primary infection. The adaptive immune responses to TcdA and TcdB following C. difficile infection remains incompletely defined. We determined that C. difficile-infected mice generate robust antibody responses to TcdA but not to TcdB. Furthermore, TcdA-responsive, but not TcdB-responsive, IL-17A producing-CD4+ T cells were detected following infection. To test if any toxin specific CD4+ T cells were present within the lamina propria, we developed a TcdB tetramer. Tetramer+ TcdB-specific CD4+ T cells were detected in the lamina propria; however, they were primarily FoxP3+ regulatory T cells. To determine whether failed immune responses to TcdB are driven by toxin activity, we utilized mutant strains of C. difficile that express enzymatically inactive (glucosyltransferase mutant [GTX]) TcdB. Infection with TcdB-GTX restored TcdB-specific antibody responses and lead to a lower regulatory T cell ratio among TcdB-specific CD4+ T cells. Taken together, these data demonstrate that the glucosyltransferase activity of TcdB hinders the adaptive immune response to TcdB. Inhibition of adaptive immunity by toxin activity may be a mechanism that underlies recurrent C. difficile infections in human patients. Funding Sources This work was funded by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants (R01AI158830 to M.C.A.; U19AI174998 to M.C.A., J.P.Z., M.G.A.; AI95755, BX002943, and AI174999 to D.B.L.). Topic Categories Mucosal and Regional Immunology (MUC)