Analysis of Flagellin-Specific Adaptive Immunity Reveals Links to Dysbiosis in Patients With Inflammatory Bowel Disease.

Background & Aims: Bacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4 ⁺ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4 ⁺ T cells. We aimed to quantify and characterize flagellin-specific CD4 ⁺ T cells in Crohn's disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity.
Methods: Blood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4 ⁺ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing.
Results: Compared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen-specific CD4 ⁺ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4 ⁺ T cells. The proportion of flagellin-specific CD4 ⁺ T cells that were CXCR3 ^neg CCR4 ⁺ CCR6 ⁺ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39 ⁺ , PD-1 ⁺ , and integrin β7 ⁺ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin.
Conclusions: Both CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4 ⁺ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4 ⁺ T cells in inflammatory bowel disease.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)