Human Blood and Mucosal Regulatory T Cells Express Activation Markers and Inhibitory Receptors in Inflammatory Bowel Disease

BACKGROUND: FOXP3(+) regulatory T cells (Tregs) are critical for preventing intestinal inflammation. However, FOXP3(+) T cells are paradoxically increased in the intestines of patients with the inflammatory bowel disease (IBD) ulcerative colitis (UC) or Crohn’s disease (CD). We determined whether these FOXP3(+) cells in IBD patients share or lack the phenotype of such cells from patients without IBD. METHODS: We quantified and characterized FOXP3(+) Treg populations, as well as FOXP3(-) CD4(+) T cells, in the lamina propria lymphocytes (LPL) of intestine surgically resected from patients with and without IBD, and in the blood of controls or Crohn’s patients with or without disease activity. RESULTS: In all samples, a similar fraction of FOXP3(+) cells expressed the “natural” Treg (nTreg) marker Helios, suggesting that, in IBD, these cells are not entirely “induced” Tregs (iTregs) derived from activated effector T cells. Helios(+) and Helios(-) FOXP3(+) T cells demonstrated similar expression of maturation markers, activation markers, and inhibitory molecules between IBD patients and controls, while FOXP3(-) cells paradoxically expressed more of the inhibitory receptors CD39, CTLA4, and PD-1 in inflamed mucosa. Greater expression of activation markers was also seen in both Helios(+) and Helios(-) Tregs, relative to FOXP3(-) cells, in both IBD patients and controls, indicating that Tregs are effectively activated by antigen in IBD. CONCLUSIONS: Extensive immunophenotyping revealed that Helios(+) and Helios(-) mucosal Tregs exist at a similar frequency, and have a similar expression of inhibitory molecules and activation markers in patients with IBD as in healthy controls.