Category: Immunity & infection
Clostridium difficile infection (CDI) is a leading cause of infectious diarrhea, with approximately 25% of patients relapsing after treatment. C.difficile pathogenicity requires the activities of its toxins, TcdA and TcdB, but the T cell-mediated response to these toxins remains uncharacterized. We enrolled a cohort of patients with newly acquired CDI, a cohort with relapsing CDI, and healthy volunteers with no history of CDI. Toxin-specific CD4+ T cell responses were measured using a whole blood flow cytometry assay that measures induced co-expression of CD25 and OX40 following 44h incubation with antigen. In patients with recurring CDI, CD4+ T cell responses to TcdB, but not TcdA, were significantly higher than for healthy controls and newly acquired CDI. In both patient cohorts, TcdB-specific CD4+ T cells were functionally heterogeneous; with a 1:1 ratio of Tregs to T effectors, and T effectors containing Th1, Th2 and Th17 cells at a 1.5:1:3 ratio. Interestingly, TcdB-specific Th1 and Th17 cells were significantly reduced in recurring, compared to newly acquired, CDI. Analysis of sorted TcdB-specific CD4+ T cells confirmed antigen specificity and polarization towards Th17 cells, important for intestinal anti-pathogen immunity. Levels of anti-TcdA/TcdB IgG antibodies were not different between patients and controls. This is the first investigation of T cell immunity to C. difficile toxins, and identifies anti-TcdB CD4+ T cells as a marker of active disease. Analysing toxin-specific CD4+ T cell responses has the potential to predict relapse and provides insight into how CD4+ T cell memory develops in response to a prevalent bacterial pathogen.
Laura Cook– University of British Columbia
May Wong– University of British Columbia
Xiaojiao Wang– University of British Columbia
William Rees– University of British Columbia
Megan Levings– Department of Surgery, University of British Columbia, University of British Columbia
Theodore Steiner– University of British Columbia