Gamma/delta T cells are the predominant source of interleukin‐17 in affected joints in collagen‐induced arthritis, but not in rheumatoid arthritis

Ito, Yoshinaga; Usui, Takashi; Kobayashi, Shio; Iguchi-Hashimoto, Mikiko; Ito, Hiromu; Yokota, Hiroyuki; Nakamura, Takashi; Shimizu, Masakazu; Kawabata, Daisuke; Yukawa, Naoichiro; Hashimoto, Motomu; Sakaguchi, Noriko; Sakaguchi, Shimon; Yoshifuji, Hajime; Nojima, Takaki; Ohmura, Koichiro; Fujii, Tomoyuki; Mimori, Tsuneyo

doi:10.1002/art.24687

Cited by 145 publications

(140 citation statements)

References 54 publications

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“…A recent report shows that V δ 2 + γδ T cells accumulate in the synovium of patients with RA and produce high levels of IL‐17 as well as IFN‐ γ 98. However, the predominance of IFN‐ γ ‐producing γδ T cells instead of γδ 17 cells in affected joints is reported elsewhere 24. This discrepancy may result from the differences of medical treatment and/or stages of RA.…”

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 95%

“…γδ 17 cells are functionally committed in the thymus, producing IL‐17 in the periphery after stimulation with IL‐1 β and IL‐23 without additional TCR stimulation 21, 24. The ‘ready‐to‐go’ phenotype of γδ 17 cells is especially efficient for early‐stage pathogen clearance.…”

Section: The Mechanism Of Il‐17 Production In γδ17 Cellsmentioning

confidence: 99%

“…In the collagen‐induced arthritis model, both γδ 17 cells and Th17 cells are found in joints and draining lymph nodes and the majority of the γδ 17 cells are V γ 4 + /V δ 4 + 22, 24. V γ 4 + cell depletion reduces Th17 cell number60 as well as arthritis severity,22 suggesting that the V γ 4 + /V δ 4 + subset aggravates disease by promoting a Th17 cell response.…”

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

“…V γ 4 + cell depletion reduces Th17 cell number60 as well as arthritis severity,22 suggesting that the V γ 4 + /V δ 4 + subset aggravates disease by promoting a Th17 cell response. Some components of heat‐killed Mycobacterium tuberculosis in complete Freund's adjuvant or inflammatory cytokines induced by the adjuvant are suggested to induce V γ 4 + /V δ 4 + cell expansion 24, 607.…”

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

“…As described, the importance of IL‐17 in the development of rheumatoid arthritis (RA) is suggested in mouse models and γδ 17 cells are accumulated in arthritic joints,7, 20, 22, 24 but the importance of γδ 17 cells in patients with RA is controversial. A recent report shows that V δ 2 + γδ T cells accumulate in the synovium of patients with RA and produce high levels of IL‐17 as well as IFN‐ γ 98.…”

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

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Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 95%

Section: The Mechanism Of Il‐17 Production In γδ17 Cellsmentioning

confidence: 99%

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Stoop¹,

Harry²,

Delwig³

et al. 2010

Arthritis & Rheumatism

122

114

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Results. Tolerogenic DCs displayed a semimature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen-pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin-10-producing CD4؉ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin-17-producing ␥/␦ T cells.Conclusion. Treatment with type II collagenpulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis.

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Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis

Courties¹,

Baron²,

Présumey³

et al. 2011

Arthritis & Rheumatism

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Objective. Several lines of evidence implicate cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA 2 ␣ inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi).Methods. Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA 2 ␣ small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed.Results. Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor ␣ secretion and lower cPLA 2 ␣ expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA 2 ␣ in CD11bϩ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-␥, but not interleukin-17, in draining lymph node cells were decreased.Conclusion. Our findings indicate that systemic RNAi-mediated cPLA 2 ␣ gene silencing in CD11bϩ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by chronic systemic inflammation that predominantly affects articular tissue. Among the immune cells infiltrating RA joints, monocytes are abundantly represented in the synovial fluid and tissue and are considered to be major effectors of synovial inflammation. Monocytes play a key role in both the systemic and the local progression of RA, by producing molecules that participate in the inflammatory and catabolic events in the disease (1). It was recently shown that the spleen contributes to the regulation of inflammation, through monocytes that are Drs. Apparailly and Davignon contributed equally to this work. Dr. Apparailly has provided expert testimony to AERES, the French agency for research evaluation, and to an INSERM evaluation committee (CSS6); she holds patents WO 00/73481 for AAV vectors for in vivo gene therapy in rheumatoid arthritis and PCT/EP 206/ 0056765 for the use of RNA biomarkers in rheumatoid arthritis.

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Gamma/delta T cells are the predominant source of interleukin‐17 in affected joints in collagen‐induced arthritis, but not in rheumatoid arthritis

Cited by 145 publications

References 54 publications

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis

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