Loss of CD4+ T Cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells

Gareth Wyn Jones, Rachel Mary McLoughlin, Victoria Jayne Hammond, Clare Rhian Parker, John Williams, Raj Malhotra, Jurgen Scheller, Anwen Williams, Stefan Rose-John, Nicholas Topley, Simon Arnett Jones

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) alpha subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R?deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A?secreting CD4+ T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4+ T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.
Original languageUndefined/Unknown
Pages (from-to)2130-2139
Number of pages10
JournalJournal of Immunology
Volume184
Issue number4
Publication statusPublished - 1 Feb 2010

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