Regulatory T cell proliferative potential is impaired in human autoimmune disease

Nat Med. 2014 Jan;20(1):69-74. doi: 10.1038/nm.3411. Epub 2013 Dec 8.


Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. 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 state. 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 (p27(kip1)) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / immunology*
  • Humans
  • Interleukin-2 / metabolism
  • Multiple Sclerosis, Relapsing-Remitting / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interleukin-2 / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / immunology*
  • Statistics, Nonparametric
  • T-Lymphocytes, Regulatory / immunology*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • Cyclin-Dependent Kinase Inhibitor p27