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Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease

This article was retracted on 05 December 2013

A Retraction to this article was published on 05 December 2013

This article has been updated

Abstract

Interleukin-7 receptor (IL-7R) is genetically associated with susceptibility to multiple sclerosis. Here we describe that IL-7 is essential for survival and expansion of pathogenic T helper type 17 (TH17) cells in experimental autoimmune encephalomyelitis (EAE). IL-7 directly expanded effector TH17 cells in EAE and human TH17 cells from subjects with multiple sclerosis, whereas it was not required for TH17 differentiation. IL-7R antagonism rendered differentiated TH17 cells susceptible to apoptosis through the inhibition of Janus kinase–signal transducer and activator of transcription-5 (JAK-STAT5) pathway and altered expression of the prosurvival protein Bcl-2 and the proapoptotic protein Bax, leading to decreased severity of EAE. In contrast, TH1 and regulatory T (Treg) cells were less susceptible to or not affected by IL-7R antagonism in vivo. The selectivity was attributable to minimal expression of IL-7Rα in Treg cells and correlated with a high level of Socs1 (encoding suppressor of cytokine signaling-1) expression in TH1 cells. The study reveals a unique, previously undescribed role of IL-7–IL-7R in TH17 cell survival and expansion and has implications in the treatment of autoimmune disease.

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Figure 1: Amelioration of EAE by IL-7R antagonism through selective reduction of TH17 cells.
Figure 2: The role of IL-7 in TH17 differentiation.
Figure 3: Requirement for IL-7 in TH17 cell expansion through JAK-STAT5.
Figure 4: Mechanism underlying the survival of differentiated TH17 cells mediated by IL-7.
Figure 5: Selectivity in susceptibility of TH17, TH1 and Treg cells to IL-7R antagonism through differential expression of IL-7Rα and Socs1.
Figure 6: Effects of IL-7 and IL-7Rα antagonism on survival and expansion of TH17 cells derived from subjects with multiple sclerosis.

Change history

  • 05 December 2013

    The above manuscript was authored by scientists from the GlaxoSmithKline (GSK) Research and Development Center in Shanghai, China, and a researcher from Baylor Medical College who later became a GSK employee. Following anonymous reports of inaccuracies in this study, GSK conducted an investigation into these allegations.

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Acknowledgements

We thank C. Dong for critical reading of this manuscript.

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Contributions

X.L., S.L. and J.Z.Z. designed and discussed the study; X.L., C.W. and Z.T. performed the majority of the T cell experiments; J.W. performed viral gene expression experiments; Y.Z. performed EAE mouse experiments; B.W., X.Q. and L.L. performed the adoptive transfer experiments; R.L. and H.P. performed immunoblotting experiments; M.S. and A.L. performed histopathology analyses; J.H. performed human in vitro experiments; X.L., S.L., T.B.G., L.F., H.L. and J.Z.Z. contributed to the writing of the paper; J.Z.Z. supervised the project.

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Correspondence to Jingwu Z Zhang.

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GlaxoSmithKline Research and Development Center is a division of GlaxoSmithKline. All authors except J.H. were employed by GlaxoSmithKline at the time of these studies.

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Liu, X., Leung, S., Wang, C. et al. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med 16, 191–197 (2010). https://doi.org/10.1038/nm.2077

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