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Regulatory T cell proliferative potential is impaired in human autoimmune disease

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A Corrigendum to this article was published on 06 February 2014

This article has been updated

Abstract

Human CD4+CD25highCD127FoxP3+ regulatory T (Treg) cells suppress immune responses in vitro and in vivo1. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders2,3. Treg cells represent the most actively replicating compartment within the CD4+ cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state4,5. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)–signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27kip1) and extracellular signal–related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.

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Figure 1: Impaired proliferation of Treg cells in subjects with RRMS is associated with altered IL-2 secretion.
Figure 2: Impairment of the IL-2-IL-2R–STAT5 signaling pathway in Treg cells from subjects with RRMS.
Figure 3: Altered FoxP3 p-S6, p-ERK1/2 and p27kip-1 abundance in Treg cells from subjects with RRMS.
Figure 4: Correlation between Treg cell proliferative potential and RRMS clinical disease stage.

Change history

  • 17 January 2014

     In the version of this article published, the data points on the graph in Figure 2g were incorrectly labeled. The black data points should be Controls and the gray data points should be RRMS. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work is supported by grants from Fondazione Italiana Sclerosi Multipla (FISM) 2012/R/11, the European Union IDEAS Programme European Research Council Starting Grant “menTORingTregs” 310496, the Ministero della Salute Grant GR-2010-2315414 and the Fondo per gli Investimenti della Ricerca di Base (FIRB) grant RBFR12I3UB_004; A.L.C. is supported by the US National Institutes of Health grant AI95921. The authors thank S. De Simone and M. Galgani from the MoFlo Cell Sorting Facility and C. La Rocca for assistance in the Treg cell isolations. This work is dedicated to the memory of E. Papa and S. Zappacosta.

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Contributions

G.M. designed the research; F.C., V.D.R. and C.P. performed the research; G.M., F.C., V.D.R., P.B.C., S.M., A.P., D.B. and A.L.C. analyzed the data and interpreted results; D.B. and A.P. performed statistical analyses; P.B.C. and S.M. recruited subjects with RRMS and analyzed clinical data and G.M., F.C., V.D.R. and A.L.C. wrote the paper.

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Correspondence to Giuseppe Matarese.

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The authors declare no competing financial interests.

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Carbone, F., De Rosa, V., Carrieri, P. et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med 20, 69–74 (2014). https://doi.org/10.1038/nm.3411

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