IL-7/IL-7 Receptor Signaling Differentially Affects Effector CD4+ T Cell Subsets Involved in Experimental Autoimmune Encephalomyelitis

Abstract

IL-17-producing CD4+ T (Th17) cells, along with IFN-gamma-expressing Th1 cells, represent two major pathogenic T cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved in the development and effector functions of Th1 and Th17 cells have been largely characterized. Among them, IL-23 is essential for the generation of stable and encephalitogenic Th17 cells and for the development of EAE. The IL-7/IL-7R signaling axis participates in cell survival, and perturbation of this pathway has been associated with enhanced susceptibility to MS. A link between IL-23-driven pathogenic T cells and IL-7/IL-7R signaling has previously been proposed but has not been formally addressed. In the present study, we showed that Th17 cells from mice with EAE express high levels of IL-7Ralpha compared to Th1 cells. Using mice that constitutively express IL-7Ralpha on T cells, we determined that sustained IL-7R expression in IL-23R deficient mice could not drive pathogenic T cells and the development of EAE. IL-7 inhibited the differentiation of Th17 cells but promoted IFN-gamma and GM-CSF secretion in vitro. In vivo IL-7/anti-IL-7 mAb complexes selectively expanded and enhanced the proliferation of CXCR3-expressing Th1 cells but did not impact Th17 cells and EAE development in wild-type and IL-23R-deficient mice. Importantly, high IL-7 expression was detected in the CNS during EAE and could drive the plasticity of Th17 cells to IFN-gamma-producing T cells. Together, these data address the contribution of IL-23/IL-23R and IL-7/IL-7R signaling in Th17 and Th1 cell dynamics during CNS autoimmunity.

Sialomucin CD43 regulates T helper type 17 cell intercellular adhesion molecule 1 dependent adhesion, apical migration and transendothelial migration

“…Selectin–selectin ligand interactions, on the other hand, are dispensable for the development of EAE . Numerous findings support the view that Th17 cells play an essential role in triggering the initial phases of autoimmune CNS inflammation, whereas Th1 cells likely contribute to pathogenesis later in disease progression . Although different T‐cell subsets use a similar repertoire of ligands to traffic to sites of inflammation, their expression patterns can differ, resulting in selective recruitment .…”

“…[6][7][8] Numerous findings support the view that Th17 cells play an essential role in triggering the initial phases of autoimmune CNS inflammation, whereas Th1 cells likely contribute to pathogenesis later in disease progression. 1,[9][10][11] Although different T-cell subsets use a similar repertoire of ligands to traffic to sites of inflammation, their expression patterns can differ, resulting in selective recruitment. 4,12 Hence, it is critical to identify the adhesion molecules that mediate such selective recruitment.…”

IL‐7/IL‐7R signaling pathway might play a role in recurrent pregnancy losses by increasing inflammatory Th17 cells and decreasing Treg cells

“…This suggests that regulation of IL‐7/IL‐7R signaling pathway may be a new therapeutic strategy for RPL. IL‐7 is a key modulator for the differentiation of effector T cells, especially inducing Th17 cell proliferation in autoimmune diseases, such as autoimmune encephalitis and MS . Recent clinical trials using recombinant IL‐7 have shown an IL‐7‐dose‐dependent increase in CD8 + and CD4 + T cell numbers, but a relative decrease in CD4 + Treg cells .…”

“…IL‐7 is a key cytokine which is required for the proliferation and survival of pathogenic Th17 cells and as such has been shown to promote autoimmune diseases, for instance, experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) . In autoimmune diseases mouse model, blockade of IL‐7R by IL‐7R antagonist prevented Th17 cell differentiation that led to decreased severity of arthritis, reduced joint damage, and decreased pro‐inflammatory cytokines and other mediators associated with tissue damage .…”

The GPR17 Receptor—A Promising Goal for Therapy and a Potential Marker of the Neurodegenerative Process in Multiple Sclerosis

“…Also, T-helper type 1 (Th1) cells, characterized by the production of interferon gamma (IFN-γ), are considered a type of effector Th cell that mediates the pathogenesis of MS [24]. Th17 cells are at least as crucial as Th1 cells in this disease [25,26].…”