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 FOXP3(-)CD4(+) 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.