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

Harrington, Laurie E.; Hatton, Robin D.; Mangan, Paul R.; Turner, Henrietta; Murphy, Theresa L.; Murphy, Kenneth M.; Weaver, Casey T.

doi:10.1038/ni1254

Cited by 4,141 publications

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“…This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of IL-17 [2,3].…”

Section: Introductionmentioning

confidence: 67%

“…More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of IL-17 [2,3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4].…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasmacytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, antierythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b + cells that produced IL-6. We also generated IL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasmacytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production. Eur. J. Immunol. 2012Immunol. . 42: 1999Immunol. -2009 Introduction CD4 + T helper (Th) cells are a subcategory of T lymphocytes that play a central role in modulating immune responses. Classically, naïve CD4 + T cells have been thought to differentiate into two cell types, Th1 and Th2 cells. This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al. [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of 3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4]. Expression of the transcription factor retinoic acid related orphan receptor gamma-t (RORγt) is required for the differentiation of Th17 cells [5,6]. The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11]. Since its discovery i...

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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“…Th cells producing IL-17 (Th17 cells) are a distinct subset of effector cells that differentiate from naive T cells in response to IL-6 and TGF-b [25,26], whereas IL-23 serves as an important factor to expand previously differentiated Th17 cell populations and gd T cells [27,28]. Our data showed that C5a significantly increased IL-17 production by T lymphocytes in the presence of DC, while it had no influence on IL-17 production from T lymphocyte when DC were absent.…”

Section: Discussionmentioning

confidence: 99%

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Xu¹,

Wang²,

Han³

et al. 2010

Eur J Immunol

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Complement 5a (C5a) and are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by cd T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by cd T cells. Dendritic cells (DC) were found to act as a ''bridge'' between C5a and cd T cells in a mechanism involving IL-6 and transforming growth factor b (TGF-b). These results imply that C5a affects the crosstalk between DC and cd T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17.Key words: Complement system . gd T cells . Immunopathology IntroductionSepsis is a life-threatening medical condition caused by various microorganisms entering the human bloodstream and triggering an uncontrolled inflammatory reaction. In light of the multifactorial pathogenesis of sepsis, extensive work has been done to characterize the numerous agents and mediators that are involved in sepsis. In spite of extensive research efforts over the last 20 years, sepsis remains the leading cause of death in intensive care units [1,2]. Specific therapies are generally unavailable because pathogenic mechanisms are still unclear.There is abundant evidence that complement activation, production of cytokines and other inflammatory responses occur in sepsis [3]. It is generally accepted that the complement activation product complement 5a (C5a) plays an important inflammatory role in rodents following cecal ligation and puncture (CLP) [4]. C5a exerts its effects through the high-affinity C5a receptor (C5aR) and C5L2. C5L2, a putative ''default'' receptor, has been suggested to play important role in balancing the biological effect of C5a. For example, recent data showed that both C5aR and C5l2 cooperatively play functional parts in the setting of sepsis [5]. It has been shown that blockade of C5a or its receptor (C5aR) can inhibit the development of CLP and is associated with decreased levels of bacteria, preservation of innate immune functions of blood neutrophils, reduced thymocyte apoptosis and greatly improved survival rates [6,7].IL-17 (also known as IL-17A) is a proinflammatory cytokine produced by a variety of cells including CD4 1 Th17 cells, CD8 1 T cells, neutrophils and NK cells [8]. Recent reports also suggested that gd T cells are a major source of . Although it has been demonstrated that IL-17 plays an important role in Ã These authors contributed equally to this paper. Understanding crosstalk between critical pathogenic factors may be very important for designing treatments for sepsis. Here, we studied the crosstalk between two critical pathogenic factors, C5a and IL-17. Our results show that C5a acted on DC, which subsequently induced gd T cells to secrete IL-17. ResultsC5a induced IL-17 in CLP-induce...

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“…Recently, Th17 cells are described as a further specialized subset of CD4 1 effector cells in addition to the well-known Th1 and Th2 cells [1][2][3]. Upon stimulation Th17 cells acquire the capacity to produce the inflammatory cytokine IL-17 [4].…”

Section: Introductionmentioning

confidence: 99%

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

et al. 2009

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

Cited by 4,141 publications

References 51 publications

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

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