Regulatory T cell proliferative potential is impaired in human autoimmune disease

Fortunata Carbone, Veronica De Rosa, Pietro B. Carrieri, Silvana Montella, Dario Bruzzese, Antonio Porcellini, Claudio Procaccini, Antonio La Cava, Giuseppe Matarese

Research output: Contribution to journalArticlepeer-review

Abstract

Human CD4 + CD25 high CD127 - FoxP3 + regulatory T (T reg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral T reg cells has been previously reported in autoimmune disorders. T reg 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 T reg 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 T reg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in T reg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of T reg cells in autoimmune disease.

Original languageEnglish
Pages (from-to)69-74
Number of pages6
JournalNature Medicine
Volume20
Issue number1
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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