T-cell Receptor Sequencing Reveals the Clonal Diversity and Overlap of Colonic Effector and FOXP3+ T Cells in Ulcerative Colitis

BACKGROUND: FOXP3 regulatory T cell prevent inflammation but are paradoxically increased in ulcerative colitis (UC). Local T-cell activation has been hypothesized to account for increased FOXP3 expression in colon lamina propria (LP) T cells. METHODS: To see if human FOXP3 LP T cells are an activated fraction of otherwise FOXP3 effector T cells and explore their clonal diversity in health and disease, we deep sequenced clonally unique T-cell receptor hypervariable regions of FOXP3 and FOXP3CD4 T-cell subpopulations from inflamed versus noninflamed colon LP or mesenteric lymph nodes of patients with or without UC. RESULTS: The clonal diversity of each LP T-cell population was not different between patients with versus without UC. Repertoire overlap was only seen between a minority of FOXP3 and FOXP3 cells, including recently activated CD38 cells and Th17-like CD161 effector T cells, but this repertoire overlap was not different between patients with versus without UC and was no larger than the overlap between Helios and Helios FOXP3 cells. CONCLUSIONS: Thus, at steady state, only a minority of FOXP3, and particularly Helios, T cells share a T-cell receptor sequence with FOXP3 effector populations in the colon LP, even in UC, revealing distinct clonal origins for LP regulatory T cell and effector T cells in humans.