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

Michael P Crawford; Sushmita Sinha; Pranav S Renavikar; Nicholas Borcherding; Nitin J Karandikar

doi:10.1073/pnas.2005010117

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

Journal article

Open access

Peer reviewed

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

Michael P Crawford, Sushmita Sinha, Pranav S Renavikar, Nicholas Borcherding and Nitin J Karandikar

Proceedings of the National Academy of Sciences - PNAS, Vol.117(32), pp.19408-19414

08/11/2020

DOI: 10.1073/pnas.2005010117

PMCID: PMC7430972

PMID: 32719138

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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.

CD4-Positive T-Lymphocytes - immunology

CD8-Positive T-Lymphocytes - immunology

Cell Differentiation

Humans

Immune Tolerance - immunology

Interleukin-17 - immunology

Interleukin-17 - metabolism

Interleukin-1beta - metabolism

Interleukin-6 - metabolism

Signal Transduction

STAT3 Transcription Factor - metabolism

T-Lymphocyte Subsets - immunology

Th17 Cells - immunology

Details

Title: Subtitle: CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression
Creators: Michael P Crawford - University of Iowa
Sushmita Sinha - University of Iowa
Pranav S Renavikar - University of Iowa
Nicholas Borcherding - University of Iowa
Nitin J Karandikar - University of Iowa
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.117(32), pp.19408-19414
DOI: 10.1073/pnas.2005010117
PMID: 32719138
PMCID: PMC7430972
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: R01 AI121567 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 08/11/2020
Academic Unit: Dermatology; Pathology
Record Identifier: 9984186425802771

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