Loss of STAT3 in CD4+ T Cells Prevents Development of Experimental Autoimmune Diseases

Liu, Xuebin; Lee, Yun Sang; Yu, Cheng-Rong; Egwuagu, Charles E.

doi:10.4049/jimmunol.180.9.6070

Cited by 256 publications

(247 citation statements)

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“…By day 21-28, there was a substantial reduction in inflammatory cells in the retina with diminution of clinical symptoms of disease occurring thereafter. Consistent with the requirement of STAT3 for Th17 development, STAT3KO mice did not develop EAU [19] and pathologic lesions in WT mice retina correlated temporally with increase in Th17 in LNs (Fig. 2B).…”

Section: Th17-dp Cells Persist In Peripheral Tissues After Recovery Fsupporting

confidence: 75%

“…Specifically, we investigated whether Th17-DP is present in blood, LNs or retina of mice with EAU, a model of uveitis [14]. STAT3KO mice and WT mice were immunized with interphotoreceptor-retinoid-binding-protein (IRBP) in CFA and EAU was assessed by histology [19]. In line with the previous reports, initial signs of EAU appeared 7-12 d after immunization, with full-blown disease developing by day 14-16 post-immunization ( Fig.…”

Section: Th17-dp Cells Persist In Peripheral Tissues After Recovery Fmentioning

confidence: 99%

“…The Th17 lineage is characterized by a unique transcriptional program induced by STAT3; mice conditionally deficient in STAT3 in the CD4 1 T-cell compartment (STAT3KO) cannot generate Th17 and do not develop EAU or EAE, underscoring the requirement of STAT3 for developing Th17-mediated diseases [17][18][19]. In view of the pivotal role of IL-2 in the proliferation or survival of mouse Th1, Th2 and Treg cell subsets and in the expansion of human Th17, it is puzzling that IL-2 inhibits differentiation of mouse Th17 cells [20].…”

Section: Introductionmentioning

confidence: 99%

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Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Golestaneh

et al. 2011

Eur J Immunol

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Compared with other T‐helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL‐2 levels during Ag‐priming and this correlated with their decreased susceptibility to activation‐induced cell death (AICD). However, complete depletion of IL‐2 with IL‐2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL‐2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL‐2 (Th17‐DP). The Th17‐DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17‐DP and are targets of daclizumab, an IL‐2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL‐2 production to levels that cannot provoke IL‐2‐induced AICD yet are sufficient to promote Th17 homeostatic expansion.

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Section: Th17-dp Cells Persist In Peripheral Tissues After Recovery Fsupporting

confidence: 75%

Section: Th17-dp Cells Persist In Peripheral Tissues After Recovery Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Golestaneh

et al. 2011

Eur J Immunol

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“…Therefore, T cells other than CD4 1 Th cells secrete IL-17 and function in autoimmunity and protective immunity to pathogens and the term 'Th17' should only be used when it is shown that IL-17 is produced by CD4 1 T cells. Furthermore, while Th17 can be clearly identified as a distinct population of CD4 1 T cells from Th1 cells and to employ distinct transcriptional factors for their development, a population of cells that coexpress IL-17 and IFN-g have been identified [32][33][34]. IL-17 1 IFN-g 1 CD4 1 and IL-17 1 IFN-g À CD4 1 T cells express receptors for both IL-12 and IL-23, and stimulation with IL-12 enhances IFN-g production and T-bet expression [35].…”

Section: T-cell Subtypes That Secrete Il-17mentioning

confidence: 99%

“…STAT-3 has been shown to regulate IL-6 and IL-23 induced expression of RORgt and IL-17 production by CD4 1 T cells [66,67]. Furthermore STAT3-defective mice have reduced IL-17 production and are resistant to the development of experimental autoimmune uveoretinitis [33]. It has also been suggested that the NFAT and MAP kinase pathways are involved TCR-induced IL-17 production by human T cells [68].…”

Section: Intracellular Signalling Molecules and Transcription Factorsmentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin‐6/STAT‐3 Pathway

Maeda

Kosugi

Sato

et al. 2015

Arthritis & Rheumatology

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Objective Interleukin‐17 (IL‐17)–producing T cells (Th17 cells) play critical roles in the pathogenesis of immune‐related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN. Methods Injections of pristane (2,6,10,14‐tetramethylpentadecane [TMPD]) were administered to Bsg−/− or Bsg+/+ mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens. Results Pristane induced LN more strikingly in Bsg−/− mice than in Bsg+/+ mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg−/− mice. The expression of IL‐17 was also increased in the kidneys of Bsg−/− mice, in proportion to LN disease activity. Furthermore, treatment with anti–IL‐17 antibody reduced LN disease activity in Bsg−/− mice. Complementary to these phenotypes of Bsg−/− mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT‐3 phosphorylation during this differentiation. Moreover, STAT‐3 phosphorylation was suppressed by crosslinking of Bsg with its antibody. Conclusion Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL‐6/STAT‐3 pathway.

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Loss of STAT3 in CD4+ T Cells Prevents Development of Experimental Autoimmune Diseases

Cited by 256 publications

References 25 publications

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Induction, function and regulation of IL‐17‐producing T cells

CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin‐6/STAT‐3 Pathway

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