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Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions
  1. Alexis Mathian1,2,3,
  2. Christophe Parizot4,
  3. Karim Dorgham1,3,
  4. Salim Trad2,3,
  5. Laurent Arnaud1,2,3,
  6. Martin Larsen1,3,
  7. Makoto Miyara1,2,3,4,
  8. Miguel Hié2,
  9. Jean-Charles Piette2,3,
  10. Camille Frances3,
  11. Hans Yssel1,
  12. Zahir Amoura1,2,3,
  13. Guy Gorochov1,2,4
  1. 1(INSERM) UMR-S 945, Paris, France
  2. 2AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Department of Internal Medicine 2, Paris, France
  3. 3Université Pierre et Marie Curie, Univ Paris 6, Pole 3m, Paris, France
  4. 4AP-HP, Groupement Hospitalier Pitié-Salpêtrièr, Department of Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), CHU Pitié-Salpêtrière, Paris, France
  1. Correspondence to Guy Gorochov, Groupement Hospitalier Pitié-Salpêtrière, Department of Immunology, boulevard de l’hôpital, Paris, France, 75013; guy.gorochov{at}psl.aphp.fr

Abstract

Objective Transforming growth factor-β is considered to play a key role in the process of fibrosis in systemic sclerosis (SSc) and in the development of regulatory T cells (Treg) and pro-inflammatory Th17 T cells producing interleukin 17 (IL-17) and IL-22. The authors therefore postulated that SSc could be characterised by a marked Treg/Th17 imbalance. Previous works did not distinguish between the different subsets of Treg and the non-regulatory FoxP3+ cells leading to inconsistent results.

Methods Combined phenotypic and functional analysis of Th17 cells and FoxP3+CD4 T cells, discriminating activated Tregs and resting Tregs from non-regulatory FoxP3+ T cells, in blood and skin of SSc patients.

Results In early disease stages, there is a decreased proportion of activated Tregs. A concomitant resting Treg deficit becomes more apparent with disease progression. Active and diffuse forms of the disease are characterised by a relatively higher proportion of all FoxP3+ subsets, including non-regulatory T cells. No peripheral or local IL-17 amplification was observed. However, the authors found significantly increased IL-22 transcription levels in SSc lesional skin, as compared with healthy skin. Cytofluorometry confirmed the existence in SSc patients and controls of a distinct subset of T cells producing IL-22 in the absence of IL-17.

Conclusion SSc pathogenesis does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg defect. Active and diffuse forms of the disease are associated with a FoxP3 signature. Altogether, our data depict a status of regulatory/pro-inflammatory T cell imbalance in SSc.

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Footnotes

  • AM, CP and KD contributed equally to this work as first authors. ST and LA contributed equally to this work as second authors.

  • Funding This study was supported by Assistance Publique-Hôpitaux de Paris (CIB Pitié-Salpêtrière) and by the Institut National de la Santé et de la Recherche Médicale. M Larsen was supported by the European FP6 ‘ATTACK’ programme (contract: LSHC-CT-2005-018914) and S Trad by the Association pour la Recherche sur le Cancer.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Approval provided by the local ethics committee of the Pitié-Salpêtrière hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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