Induction and molecular signature of pathogenic TH17 cells

Lee, Youjin; Awasthi, Amit; Yosef, Nir; Quintana, Francisco J.; Xiao, Sheng; Peters, Anneli; Wu, Chuan; Kleinewietfeld, Markus; Kunder, Sharon; Hafler, David A.; Sobel, Raymond A.; Regev, Aviv; Kuchroo, Vijay K.

doi:10.1038/ni.2416

Cited by 1,012 publications

(1,237 citation statements)

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“…57,58 Further, it is becoming more apparent that the T H 17-cell lineage has a degree of heterogeneity with regards to pathogenicity. For example, T H 17 cells differentiated in the presence of TGFb are less pathogenic and produce higher levels of IL-10, whereas cells differentiated in the presence of IL-23 are more pathogenic and can produce IFN-g. 59,60 In addition, T H 17 cells have a degree of plasticity and fate-mapping studies have shown that ''ex-T H 17'' cells lose their ability to produce IL-17A altogether and exclusively produce IFN-g under certain conditions. 61 As our studies show increased production of IL-17A from T H 17 cells and a lack of pathogenicity in multiple mouse models of intestinal inflammation, we hypothesize that in the absence of HIC1, T H 17 cells are skewed to a more protective lineage and do not transition into pathogenic cells.…”

Section: Hic1 Is Required To Limit Stat3 Signaling In T H 17 Cellsmentioning

confidence: 99%

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

et al. 2017

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Section: Hic1 Is Required To Limit Stat3 Signaling In T H 17 Cellsmentioning

confidence: 99%

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

et al. 2017

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“…Transfer of Ldlr −/− Il23r −/− CD4 + T cells to Ldlr −/− Rag1 −/− recipient mice resulted in reduced levels of Th17 and IL‐17 + IFN‐γ + Th17 cells, demonstrating that IL‐23 plays a role in promoting Th17 responses during lymphopenia‐induced proliferation, but failed to reduce atherosclerosis. These results indicate that the IL‐23‐dependent differentiation of “pathogenic” Th17 effector cells, which has been shown to contribute to inflammation and tissue damage in chronic autoimmune disease,6, 7 does not have significant effects on atherosclerosis in Ldlr −/− mice. Moreover, in hypercholesterolemic nonlymphopenic mice, levels of IL‐17 + IFN‐γ + double‐producing Th17 cells are very low (≈0.05% of CD4 + T helper cells), further suggesting that this cell population is not a key player in atherosclerosis.…”

Section: Discussionmentioning

confidence: 76%

“…5, 6, 7 IL‐23 signals through the IL‐23 receptor to stabilize and promote production of IL‐17 and IFN‐γ in Th17 cells 5. Furthermore, IL‐23 is required for the generation of “pathogenic” IL‐17 + IFN‐γ + double‐producing helper T cells that mediate tissue damage in models of autoimmune disease 8, 9.…”

Section: Introductionmentioning

confidence: 99%

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

Engelbertsen

Depuydt

Verwilligen

et al. 2018

JAHA

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BackgroundInterleukin‐23 (IL‐23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL‐23 receptor (IL‐23R)‐expressing cells in the atherosclerotic aorta and evaluated the effect of IL‐23R deficiency on atherosclerosis development in mice.Methods and ResultsWe used heterozygous Ldlr −/− Il23r e GFP / WT knock‐in mice to identify IL‐23R‐expressing cells by flow cytometry and homozygous Ldlr −/− Il23r e GFP / eGFP (Ldlr −/− Il23r −/−) mice to investigate the effect of lack of IL‐23R in atherosclerosis. We demonstrate the presence of relatively rare IL‐23R‐expressing cells in lymphoid tissue and aorta (≈0.1–1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high‐fat diet, production of IL‐17, but not interferon‐γ, by CD4+ T cells and other lymphocytes was reduced in Ldlr −/− Il23r −/− compared with Ldlr −/−controls. However, Ldlr −/− and Ldlr −/− Il23r −/− mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL‐23R‐deficient CD4+ T cells to lymphopenic Ldlr −/− Rag1 −/− resulted in dramatically reduced IL‐17‐producing T cells but did not reduce atherosclerosis, compared with transfer of IL‐23R‐sufficient CD4+ T cells.ConclusionsThese data demonstrate that loss of IL‐23R does not affect development of experimental atherosclerosis in LDLr‐deficient mice, despite a role for IL‐23 in differentiation of IL‐17‐producing T cells.

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“…Th17 cells can directly target neurons [44], and under conditions of stress in vitro, neurons express IL-17 receptor and treatment with IL-17 can induce neuronal cell death [45]. GM-CSF has also been identified as a potential mediator of neural damage [46][47][48][49]. GM-CSF activates microglial cells and recruits myeloid cells into the CNS, but the mechanism by which this leads to disease has not been identified [47,50,51].…”

Section: Role Of Virus Strainmentioning

confidence: 99%

Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage

Griffin

2016

Neurotherapeutics

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Mosquito-borne viruses are important causes of death and long-term neurologic disability due to encephalomyelitis. Studies of mice infected with the alphavirus Sindbis virus have shown that outcome is dependent on the age and genetic background of the mouse and virulence of the infecting virus. Agedependent susceptibility reflects the acquisition by neurons of resistance to virus replication and virus-induced cell death with maturation. In mature mice, the populations of neurons most susceptible to infection are in the hippocampus and anterior horn of the spinal cord. Hippocampal infection leads to long-term memory deficits in mice that survive, while motor neuron infection can lead to paralysis and death. Neuronal death is immune-mediated, rather than a direct consequence of virus infection, and associated with entry and differentiation of pathogenic T helper 17 cells in the nervous system. To modulate glutamate excitotoxicity, mice were treated with an N-methyl-D-aspartate receptor antagonist, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists or a glutamine antagonist. The N-methyl-D-aspartate receptor antagonist MK-801 protected hippocampal neurons but not motor neurons, and mice still became paralyzed and died. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists GYKI-52466 and talampanel protected both hippocampal and motor neurons and prevented paralysis and death. Glutamine antagonist 6-diazo-5-l-norleucine protected hippocampal neurons and improved memory generation in mice surviving infection with an avirulent virus. Surprisingly, in all cases protection was associated with inhibition of the antiviral immune response, reduced entry of inflammatory cells into the central nervous system, and delayed virus clearance, emphasizing the importance of treatment approaches that include prevention of immunopathologic damage.

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Induction and molecular signature of pathogenic TH17 cells

Cited by 1,012 publications

References 50 publications

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage

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