Ex vivo IL-1 receptor type I expression in human CD4+ T cells identifies an early intermediate in the differentiation of Th17 from FOXP3+ naive regulatory T cells

C Raffin, I Raimbaud, D Valmori… - The Journal of …, 2011 - journals.aai.org
C Raffin, I Raimbaud, D Valmori, M Ayyoub
The Journal of Immunology, 2011journals.aai.org
Abstract IL-17–producing CD4+ Th (Th17) cells are a unique subset of proinflammatory cells
expressing the retinoic acid-related orphan receptor γt and associated with different forms of
inflammatory autoimmune pathologies. The development of Th17 cells, mediated by TGF-β
and IL-1, is closely related to that of FOXP3+ suppressor/regulatory T cells (Treg). In this
study, we report that ex vivo expression of IL-1RI in human circulating CD4+ T cells identifies
a subpopulation of FOXP3+ Treg that coexpress retinoic acid-related orphan receptor γt …
Abstract
IL-17–producing CD4+ Th (Th17) cells are a unique subset of proinflammatory cells expressing the retinoic acid-related orphan receptor γt and associated with different forms of inflammatory autoimmune pathologies. The development of Th17 cells, mediated by TGF-β and IL-1, is closely related to that of FOXP3+ suppressor/regulatory T cells (Treg). In this study, we report that ex vivo expression of IL-1RI in human circulating CD4+ T cells identifies a subpopulation of FOXP3+ Treg that coexpress retinoic acid-related orphan receptor γt, secrete IL-17, and are highly enriched among CCR7+ central memory cells. Consistent with the concept that IL-1RI expression in Treg identifies a subpopulation at an early stage of differentiation, we show that, in Th17 populations differentiated in vitro from natural naive FOXP3+ Treg, IL-1RI+ IL-17–secreting cells are central memory cells, whereas IL-1RI− cells secreting IL-17 are effector memory cells. Together with the absence of detectable IL-1RI and IL-17 expression in resting naive CD4+ T cells, these data identify circulating CCR7+ Treg expressing IL-1RI ex vivo as early intermediates along an IL-1–controlled differentiation pathway leading from naive FOXP3+ Treg to Th17 effectors. We further show that, whereas IL-1RI+ central memory Treg respond to stimulation in the presence of IL-1 by generating IL-17–secreting effectors, a significant fraction of them maintain FOXP3 expression, consistent with an important role of this population in maintaining the Treg/Th17 memory pool in vivo.
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