IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

doi:10.1084/JEM.20041257

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IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

Journal Article•DOI•

IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

Claire L. Langrish, Yi Yi Chen, Wendy M. Blumenschein, Jeanine D. Mattson, Beth Basham, Jonathan D. Sedgwick, Terrill K. McClanahan, Robert A. Kastelein, Daniel J. Cua - Show less +5 more

17 Jan 2005-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 201, Iss: 2, pp 233-240

TL;DR: Using passive transfer studies, it is confirmed that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.

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Abstract: Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-γ–producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4+ T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23–driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12–driven T cells. Using passive transfer studies, we confirm that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.

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Journal Article•DOI•

Exploring the full spectrum of macrophage activation.

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David M. Mosser¹, Justin P. Edwards¹•Institutions (1)

University of Maryland, College Park¹

01 Dec 2008-Nature Reviews Immunology

TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.

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Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

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7,384 citations

Cites background from "IL-23 drives a pathogenic T cell po..."

...For example, IL-1 , IL-6 and IL-23 are produced by classically activated macrophages and have been associated with the development and expansion of T H 17 cell...
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Journal Article•DOI•

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

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Estelle Bettelli¹, Yijun Carrier², Wenda Gao¹, Thomas Korn², Terry B. Strom¹, Mohamed Oukka², Howard L. Weiner², Vijay K. Kuchroo² - Show less +4 more•Institutions (2)

Harvard University¹, Brigham and Women's Hospital²

11 May 2006-Nature

TL;DR: It is shown that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β, and the data demonstrate a dichotomy in thegeneration of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T Cells that inhibit autoimmune tissue injury.

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Abstract: On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

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6,643 citations

Journal Article•DOI•

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

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Ivaylo I. Ivanov¹, Brent S. McKenzie², Liang Zhou¹, Carlos E. Tadokoro¹, Alice Lepelley¹, Juan J. Lafaille¹, Daniel J. Cua², Dan R. Littman¹ - Show less +4 more•Institutions (2)

New York University¹, Schering-Plough²

22 Sep 2006-Cell

TL;DR: It is shown that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage of proinflammatory T helper cells and its potential as a therapeutic target in inflammatory diseases is highlighted.

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4,616 citations

Cites background from "IL-23 drives a pathogenic T cell po..."

..., 2003), transfer of cells that produce IL-17 results in severe disease (Langrish et al., 2005), and treatment of mice with a neutralizing anti-IL-17 mAb suppresses CNS autoimmune inflammation (Langrish et al....
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...Since Th17 cells have been shown recently to be the major pathogenic population in several models of autoimmune inflammation, including EAE Cell 1 (Langrish et al., 2005; Park et al., 2005), we investigated the role of RORgt in this model....
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...Only following in vivo priming does in vitro stimulation of T cells with antigen and antigen-presenting cells plus IL-23 result in effective expansion of Th17 cells (Langrish et al., 2005; Murphy et al., 2003; Veldhoen et al., 2006)....
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...IL-23 is also involved in Th17 cell differentiation, but naı̈ve T cells are IL-23 receptor negative and relatively refractory to IL-23 stimulation (Langrish et al., 2005; Oppmann et al., 2000)....
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...…termed Th17 cells, was initially shown to be dependent on the presence, during antigen stimulation, of IL-23 produced by the antigen-presenting cells (Aggarwal et al., 2003; Harrington et al., 2005; Langrish et al., 2005; 6, 1121–1133, September 22, 2006 ª2006 Elsevier Inc. 1121 Park et al., 2005)....
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Journal Article•DOI•

Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

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Laurie E. Harrington¹, Robin D. Hatton¹, Paul R. Mangan¹, Henrietta Turner¹, Theresa L. Murphy², Kenneth M. Murphy², Casey T. Weaver¹ - Show less +3 more•Institutions (2)

University of Alabama at Birmingham¹, Washington University in St. Louis²

02 Oct 2005-Nature Immunology

TL;DR: Findings provide a basis for understanding how inhibition of IFN-γ signaling enhances development of pathogenic TH-17 effector cells that can exacerbate autoimmunity.

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Abstract: CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

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4,616 citations

Cites background from "IL-23 drives a pathogenic T cell po..."

...In both experimental autoimmune encephalomyelitis (EAE) and type II collagen-induced arthritis, two heretofore prototypical 'T H 1' disease models, it has been found that IL-17-producing CD4 + effector T cells, not IFN-γ-producing effector cells, are pathogenic, thereby challenging the importance of classical T H 1 cells in the induction and maintenance of chronic inflammatory diseas...
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Journal Article•DOI•

IL-17 and Th17 Cells.

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Thomas Korn¹, Estelle Bettelli², Mohamed Oukka², Vijay K. Kuchroo²•Institutions (2)

Technische Universität München¹, Harvard University²

20 Mar 2009-Annual Review of Immunology

TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.

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Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...

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4,548 citations

Cites background from "IL-23 drives a pathogenic T cell po..."

...In the follow-up study (9), they showed that IL-23 expands/generates IL-17-producing T cells that are capable of inducing EAE when adoptively transferred into naive wild-type mice....
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...163 IL-21 pathogenic Blockade of IL-21 signaling by administration of IL-21R-Fc fusion protein attenuated CIA....
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...T-bet- and STAT4-deficient mice are resistant to EAE, and targeting IL-12 with polyclonal antibodies to IL-12 is an efficient therapy for EAE and CIA....
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...A stronger connection between IL23 and Th17 cells was established when investigators showed that IL-23 promotes the production of IL-17 by activated T cells (84) and that IL-23-expanded T cells are able to transfer EAE and CIA (9, 85)....
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...F or p er so na l u se o nl y. IFN-γ expression in the target tissues correlates with clinical signs in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA)....
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References

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Journal Article•DOI•

Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

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Daniel J. Cua, Jonathan P Sherlock, Yi Chen, Craig A. Murphy, Barbara L. Joyce, Brian W. P. Seymour, Linda Lucian, Wayne To, Sylvia Kwan, Tatyana Churakova, Sandra Zurawski, Maria T. Wiekowski¹, Sergio A. Lira², Sergio A. Lira¹, Daniel M. Gorman, Robert A. Kastelein, Jonathon D. Sedgwick - Show less +13 more•Institutions (2)

Schering-Plough¹, Icahn School of Medicine at Mount Sinai²

13 Feb 2003-Nature

TL;DR: It is shown that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL- 12, is the critical factor in this response.

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Abstract: Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.

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2,915 citations

"IL-23 drives a pathogenic T cell po..." refers methods in this paper

...Blood was collected and lysed (RBC lysis buffer; Sigma-Aldrich), and mononuclear cells from brains and spinal cord tissue were prepared as described previously ( 1 ) and surface stained with anti‐CD4-APC....
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...EAE. EAE was induced in female mice at 8‐12 wk and clinically assessed as described previously ( 1 ), using 100 � g MOG35-55 per mouse for B6 � 129 and C57BL/6 strains, or 80 � g PLP139-151 (PLP) per mouse for SJL strains and emulsified in CFA....
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...Mice. IL-23p19�� (IL-23‐deficient mice) and their WT controls were generated on a mixed B6 � 129 background using approaches described previously ( 1 )....
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Journal Article•DOI•

Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.

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Birgit Oppmann, Robin Lesley, Bianca Blom, Jackie C. Timans, Yuming Xu, Brisdell Hunte, Felix Vega, Nancy Yu, Jing Wang, Komal Singh, Francesca Zonin, Elena Vaisberg, Tatyana Churakova, Man ru Liu, Daniel M. Gorman, Janet Wagner, Sandra Zurawski, Yong-Jun Liu, John S. Abrams, Kevin W. Moore, Donna Rennick, Rene de Waal-Malefyt, Charles H. Hannum, J. Fernando Bazan, Robert A. Kastelein - Show less +21 more

01 Nov 2000-Immunity

TL;DR: Human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells and induces strong proliferation of mouse memory T cells.

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2,823 citations

"IL-23 drives a pathogenic T cell po..." refers background in this paper

...Although IL-23 shares a common p40 subunit with IL-12 (3), these cytokines have divergent activities....
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Journal Article•DOI•

Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells

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Chandrashekhar Pasare¹, Ruslan Medzhitov¹•Institutions (1)

Yale University¹

14 Feb 2003-Science

TL;DR: A second mechanism of immune induction by TLRs is described, which is independent of effects on costimulation, and dependent in part on interleukin-6, which was induced byTLRs upon recognition of microbial products.

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Abstract: Toll-like receptors (TLRs) control activation of adaptive immune responses by antigen-presenting cells (APCs). However, initiation of adaptive immune responses is also controlled by regulatory T cells (TR cells), which act to prevent activation of autoreactive T cells. Here we describe a second mechanism of immune induction by TLRs, which is independent of effects on costimulation. Microbial induction of the Toll pathway blocked the suppressive effect of CD4+CD25+ TR cells, allowing activation of pathogen-specific adaptive immune responses. This block of suppressor activity was dependent in part on interleukin-6, which was induced by TLRs upon recognition of microbial products.

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2,107 citations

"IL-23 drives a pathogenic T cell po..." refers background in this paper

...IL-6 produced by LPS-activated dendritic cells can turn off regulatory T cell (T reg cell) function, allowing effector T cell activation ( 35 )....
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Journal Article•DOI•

Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17

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Sudeepta Aggarwal¹, Nico Ghilardi, Ming-Hong Xie¹, Frederic J. de Sauvage, Austin L. Gurney¹ - Show less +1 more•Institutions (1)

Genentech¹

17 Jan 2003-Journal of Biological Chemistry

TL;DR: Evidence is presented that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion, which suggests that during a secondary immune response, IL- 23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles.

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1,909 citations

"IL-23 drives a pathogenic T cell po..." refers background in this paper

...Ex vivo analysis of draining LN (DLN) cells from immunized WT and IL-23p19 mice reflected the CNS data, with similar IFN- levels, but no IL-17 production by the IL-23p19 cells (2, 14, 15)....
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Journal Article•DOI•

Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation

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Craig A. Murphy, Claire L. Langrish, Yi Yi Chen, Wendy M. Blumenschein, Terrill K. McClanahan, Robert A. Kastelein, Jonathon D. Sedgwick, Daniel J. Cua - Show less +4 more

15 Dec 2003-Journal of Experimental Medicine

TL;DR: The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.

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Abstract: Interleukin (IL) 23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 affects memory T cell and inflammatory macrophage function through engagement of a novel receptor (IL-23R) on these cells. Recent analysis of the contribution of IL-12 and IL-23 to central nervous system autoimmune inflammation demonstrated that IL-23 rather than IL-12 was the essential cytokine. Using gene-targeted mice lacking only IL-12 (p35−/−) or IL-23 (p19−/−), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis. IL-23 gene-targeted mice did not develop clinical signs of disease and were completely resistant to the development of joint and bone pathology. Resistance correlated with an absence of IL-17–producing CD4+ T cells despite normal induction of collagen-specific, interferon-γ–producing T helper 1 cells. In contrast, IL-12–deficient p35−/− mice developed more IL-17–producing CD4+ T cells, as well as elevated mRNA expression of proinflammatory tumor necrosis factor, IL-1β, IL-6, and IL-17 in affected tissues of diseased mice. The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.

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1,695 citations

"IL-23 drives a pathogenic T cell po..." refers background or methods or result in this paper

...These results are consistent with papers suggesting that IL-23 is required for the development and expansion of IL-17–producing CD4 T cells (2, 16, 17)....
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...pression was quantitated by real-time PCR as described previously (2)....
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...Ex vivo analysis of draining LN (DLN) cells from immunized WT and IL-23p19 mice reflected the CNS data, with similar IFN- levels, but no IL-17 production by the IL-23p19 cells (2, 14, 15)....
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