Interleukin-17-producing T helper cells in autoimmunity

Hemdan, Nasr Y. A.; Birkenmeier, Gerd; Wichmann, Gunnar; El-Saad, Ahmed M. Abu; Krieger, Thorsten; Conrad, Karsten; Sack, Ulrich

doi:10.1016/j.autrev.2010.07.003

Cited by 128 publications

(100 citation statements)

References 127 publications

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“…[5][6][7][8] However, unregulated Th17 development and IL-17 production have been shown to contribute to the development of allergic and autoimmune diseases. 1,[9][10][11][12] Recently, Th17 cells have also been linked to cancer, but their involvement toward cancer ablation or progression varies widely depending on the type of cancer. [13][14][15][16] Therefore, characterizing the intracellular signaling within CD4 ϩ T cells that modifies Th17 development will have important clinical implications for a broad range of diseases.…”

Section: Introductionmentioning

confidence: 99%

The tyrosine phosphatase SHP-1 dampens murine Th17 development

Mauldin

Tung

Lorenz

2012

Blood

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IntroductionTh17 cells are a subset of CD4 ϩ T helper cells defined by their ability to secrete IL-17A and IL-17F. 1,2 IL-17 is an inflammatory cytokine important in mediating host defense against bacterial and fungal pathogens. 3,4 Under physiologic conditions, Th17 cells are found in the intestinal lamina propria and Peyer patches, where they are regulated by the local cytokine milieu and support responses against pathogenic bacteria and fungi. [5][6][7][8] However, unregulated Th17 development and IL-17 production have been shown to contribute to the development of allergic and autoimmune diseases. 1,[9][10][11][12] Recently, Th17 cells have also been linked to cancer, but their involvement toward cancer ablation or progression varies widely depending on the type of cancer. [13][14][15][16] Therefore, characterizing the intracellular signaling within CD4 ϩ T cells that modifies Th17 development will have important clinical implications for a broad range of diseases. To date, few studies have addressed how modifying early signaling events in CD4 ϩ T cells affects Th17 differentiation.Stimulation of naive T cells with either IL-6 plus TGF-␤ or IL-21 plus TGF-␤ leads to the activation and induction of several key transcription factors essential for Th17 differentiation, including STAT3, ROR␥t, and ROR␣. 2,9,12,17,18 The signaling cascade via the IL-6 receptor leads to the downstream activation of Jak kinases and, in turn, Jak-mediated phosphorylation of STAT3 proteins. This leads to homodimerization and translocation of STAT3 into the nucleus, where STAT3 directly binds to the il17a promoter and is required for the induction of ROR␥t. 17,19 Consistent with this, STAT3 Ϫ/Ϫ mice completely lack Th17 cells and are resistant to experimental autoimmune encephalitis. To date, a network of transcription factors has been linked to Th17 differentiation, yet modifiers of the signaling cascade from cytokine stimulation to transcription, and in turn Th17 development, are not well understood. 20 The Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1) is a cytoplasmic protein tyrosine phosphatase expressed in all hematopoietic cell lineages. Motheaten (me/me) mice are homozygous for a mutation that abrogates SHP-1 protein expression and display hematopoietic abnormalities resulting in death approximately 2 to 3 weeks after birth. SHP-1 is a negative regulator of signaling via cytokines, chemokines, growth factors, and antigens. 21 Specifically, SHP-1-deficient T cells display increased responses to TCR stimulation and concomitant hyperproliferation in ex vivo cultures. 22 However, the role of SHP-1 during Th17 cell differentiation is not known. Here, using mice in the motheaten background, as well as a new tissue-specific transgenic mouse line expressing a dominant negative mutant of SHP-1 in T cells, we demonstrate that SHP-1 naturally dampens Th17 cell development in vivo. SHP-1-deficient mice have increased percentages of Th17 cells in their Peyer patches and intestinal lamina propria, and T cells with d...

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Section: Introductionmentioning

confidence: 99%

The tyrosine phosphatase SHP-1 dampens murine Th17 development

Mauldin

Tung

Lorenz

2012

Blood

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“…Pro-and anti-inflammatory cytokines and chemokines and/or their receptors, key mediators of the effector function of T cells, appear to be centrally involved in the pathogenesis of RA [22]. It is well established that in the presence of interferon-gamma (IFN- , or IL-12 À/À mice develop collagen-induced arthritis (CIA) and other classically categorized T H 1-mediated diseases such as experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), in some cases with more severity [23]. This paradox may be 0014 explained by the discovery of a new subset of CD4 + that produce IL-17, namely T H 17 cells, which have recently been characterised in a number of inflammatory and autoimmune diseases such as RA, multiple sclerosis and systemic lupus erythematosus [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Effector T cells in rheumatoid arthritis: Lessons from animal models

Alzabin

Williams

2011

FEBS Letters

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The development of an immune response to self antigens drives naive T cells to differentiate into subsets of CD8+ and CD4+ effector cells including TH1, TH2, cells and the more recently described TH17, and regulatory T cells (Treg). Rheumatoid arthritis is an autoimmune disease that engages an uncontrolled influx of inflammatory cells to the joints, eventually leading to joint damage. The role that effector T cells play in the local or systemic maintenance of, or protection against, inflammation and subsequent joint damage is now becoming better understood through the use of animal models. In this review, we will explore the different animal models of RA, and their contribution to elucidating the role that effector T cells play in the regulation, induction, and maintenance of inflammatory joint disease. This understanding will aid in the design of more effective therapeutic strategies for rheumatoid arthritis and other autoimmune disorders.

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“…In this context, Th2 cells mediate allergies, and Th1 and Th17 cells are central to the development of autoimmunity. 5,6 To exert their functions, Th cells must be equipped with effective machinery optimized for their specific task. This includes subtype-specific effector cytokines and trafficking receptors.…”

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confidence: 99%

Stat3 Programs Th17-Specific Regulatory T Cells to Control GN

Kluger¹,

Luig²,

Wegscheid

et al. 2014

Journal of the American Society of Nephrology

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A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3Cre 3Stat3

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Interleukin-17-producing T helper cells in autoimmunity

Cited by 128 publications

References 127 publications

The tyrosine phosphatase SHP-1 dampens murine Th17 development

The tyrosine phosphatase SHP-1 dampens murine Th17 development

Effector T cells in rheumatoid arthritis: Lessons from animal models

Stat3 Programs Th17-Specific Regulatory T Cells to Control GN

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