Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6TransSignaling in the Local Maintenance of Th17 Cells

Abstract

IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) α 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.

Histone Deacetylase Inhibitors Modulate Interleukin 6-dependent CD4+ T Cell Polarization in Vitro and in Vivo

“…ϩ T cells are one of the few cell types in possession of the membrane-bound IL-6R, they are offering a possible target for the indicated regulation of T cell polarization (48). Complementary to the results presented here, it has been described that treatment of multiple myeloma cells with HDAC inhibitors resulted in down-modulation of IL-6R signaling (49,50).…”

Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions

“…Expression of IL-6Rα on naive T cells (Fig. 4A) is consistent with previous data (37). Production of the cytokine IL-4 by Tfh promotes Ab class switch (32).…”

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

“…Although activated T cells can produce autocrine IL-6, the receptor for IL-6 is expressed only on naive T cells and is down-modulated after activation (35,36). Thus, T cells that are exposed to IL-6 early in their activation differentiate into pathogenic Th17 cells.…”