CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression

Abstract

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1β, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.

Classical CD4 T cells as the cornerstone of antimycobacterial immunity

“…Furthermore, via IL-1β, and IL-6/STAT3 pathways, IL-17 has been shown to directly-without the involvement of APC or CD8 + T cells-increase CD4 T cell-resistance to immune regulation. 116 These functions contribute to the maintenance of Mtb within the lungs.…”

“…A further unique role for IL‐17 may be the regulation of hypoxic TB granulomas, 115 which may be linked to an inverse relationship with IL‐17 and TB disease in individuals with active TB. Furthermore, via IL‐1 β , and IL‐6/STAT3 pathways, IL‐17 has been shown to directly—without the involvement of APC or CD8 + T cells—increase CD4 T cell‐resistance to immune regulation 116 . These functions contribute to the maintenance of Mtb within the lungs.…”

Comprehensive evaluation of the effects of long-term cryopreservation on peripheral blood mononuclear cells using flow cytometry

“…CD4 + T cells can also be divided into four functional subtypes: T helper (Th) 1 (interferon [IFN]-γ + ), Th2 (interleukin [IL]-4 + ), Th17 (IL-17 + ), and regulatory T cells (Tregs), which express intracellular forkhead box P3 (FOXP3) and exhibit a strong suppressive function [ 6 , 7 ]. Cytokines produced by Th1, such as IFN-α, IFN-γ, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α, participate in cell immunity against pathogens and bacteria [ 8 ]. T helper 2 cell cytokines, including IL-4, IL-5, IL-6, and transforming growth factor (TGF)-β, enhance humoral immunity from allergens, bacteria, or toxins.…”

Estradiol-induced inhibition of endoplasmic reticulum stress normalizes splenic CD4 + T lymphocytes following hemorrhagic shock

“…Therefore, further investigation on the effects of E2 treatment on the lymphoid organ or the other immunocytes is warranted in the future. In addition, IL-17 produced by Th17 cells plays an important role in the intrinsic immune response, primarily through the induction of neutrophil-dominated inflammatory responses, as well as being an important component involved in tissue inflammation 37 . Similarly, CD4 + Foxp3 T cells is involved in the regulation of immune response after hemorrhagic shock 38 .…”