T-cell receptor sequencing reveals the clonal diversity and overlap of colonic effector and FOXP3+ T cells in ulcerative colitis

Abstract

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.