ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Dysregulated T cell memory to intestinal bacterial antigens in human autoimmune and infectious disease: implications for IL-17 inhibitors (#154)

Laura Cook 1 2 3 , William D Rees 1 3 , Daniel J Lisko 1 3 , May Q Wong 1 3 , Xiaojiao Wang 1 3 , Rosa V Garcia 3 4 , Megan E Himmel 4 , Hannah Peters 1 , Ernest G Seidman 5 , Brian Bressler 6 , Megan K Levings 3 4 7 , Theodore S Steiner 1 3
  1. Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
  2. Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia
  3. British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  4. Department of Surgery, The University of British Columbia, Vancouver, BC, Canada
  5. Division of Gastroenterology, McGill University, Montréal, Quebec, Canada
  6. Gastrointestinal Research Institute, Vancouver, British Columbia, Canada
  7. School of Biomedical Engineering, , The University of British Columbia, Vancouver, British Columbia, Canada

Introduction: Bacterial flagellin is a key antigen in Inflammatory Bowel Disease (IBD) pathogenesis. IBD is also characterised by intestinal dysbiosis, with patients at increased risk for Clostridioides difficile infection (CDI), an urgent threat to antimicrobial resistance. Studies of antibody responses to flagellin and C. difficile toxin protein antigens have not been clinically informative. We hypothesised CD4+ T cell responses would be of greater clinical use and may uncover unique therapeutic targets.

 

Objective: We aimed to quantify and characterise flagellin-specific and C. difficile toxin-specific CD4+ T cells in Crohn’s disease (CD) and ulcerative colitis (UC) patients in comparison to non-IBD CDI patients and healthy controls.

 

Methods and Results: Blood was collected from Crohn’s disease and ulcerative colitis patients, non-IBD patients with active CDI and healthy volunteers. Bacterial antigen-specific CD4+ T cell responses were detected in whole blood using an activation-induced marker flow cytometry assay measuring induced co-expression of CD25 and OX40 following 44h antigen stimulation. Both flagellin and toxin-specific CD4+ T cells could discriminate patients from healthy controls and were biased towards the IL-17 producing Th17 cell phenotype. 16S rDNA sequencing of IBD stool samples revealed differentially abundant bacterial species correlated with immune responses to flagellin. Flagellin-specific responses were increased in IBD patients and contained impaired Th17 cells compared to healthy controls. Strikingly, C. difficile toxin-specific Th17 cells were also significantly reduced in both IBD and CDI patients compared to healthy controls. Successful fecal microbiota transplant treatment of CDI was associated with reconstitution of the Th17 cell compartment.

 

Conclusions: A common feature of healthy immune responses to commensal and pathogenic bacterial antigens is a predominance of Th17 cells. These data may help explain the failure of IL-17 inhibitors in IBD clinical trials and highlight a need for further work into the role of Th17 cells in intestinal disease.