T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis

T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologica...

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Main Authors: Hirota, Keiji, Hashimoto, Motomu, Yoshitomi, Hiroyuki, Tanaka, Satoshi, Nomura, Takashi, Yamaguchi, Tomoyuki, Iwakura, Yoichiro, Sakaguchi, Noriko, Sakaguchi, Shimon
Format: Online
Language:English
Published: The Rockefeller University Press 2007
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118414/
id pubmed-2118414
recordtype oai_dc
spelling pubmed-21184142007-12-13 T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis Hirota, Keiji Hashimoto, Motomu Yoshitomi, Hiroyuki Tanaka, Satoshi Nomura, Takashi Yamaguchi, Tomoyuki Iwakura, Yoichiro Sakaguchi, Noriko Sakaguchi, Shimon Brief Definitive Reports This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA. The Rockefeller University Press 2007-01-22 /pmc/articles/PMC2118414/ /pubmed/17227914 http://dx.doi.org/10.1084/jem.20062259 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Hirota, Keiji
Hashimoto, Motomu
Yoshitomi, Hiroyuki
Tanaka, Satoshi
Nomura, Takashi
Yamaguchi, Tomoyuki
Iwakura, Yoichiro
Sakaguchi, Noriko
Sakaguchi, Shimon
spellingShingle Hirota, Keiji
Hashimoto, Motomu
Yoshitomi, Hiroyuki
Tanaka, Satoshi
Nomura, Takashi
Yamaguchi, Tomoyuki
Iwakura, Yoichiro
Sakaguchi, Noriko
Sakaguchi, Shimon
T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
author_facet Hirota, Keiji
Hashimoto, Motomu
Yoshitomi, Hiroyuki
Tanaka, Satoshi
Nomura, Takashi
Yamaguchi, Tomoyuki
Iwakura, Yoichiro
Sakaguchi, Noriko
Sakaguchi, Shimon
author_sort Hirota, Keiji
title T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
title_short T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
title_full T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
title_fullStr T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
title_full_unstemmed T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis
title_sort t cell self-reactivity forms a cytokine milieu for spontaneous development of il-17+ th cells that cause autoimmune arthritis
description This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.
publisher The Rockefeller University Press
publishDate 2007
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118414/
_version_ 1611414744535662592

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