期刊
NATURE MEDICINE
卷 20, 期 1, 页码 69-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3411
关键词
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资金
- Fondazione Italiana Sclerosi Multipla (FISM) [2012/R/11]
- European Union IDEAS Programme European Research Council Starting Grant [310496]
- Ministero della Salute [GR-2010-2315414]
- Fondo per gli Investimenti della Ricerca di Base (FIRB) [RBFR12I3UB_004]
- US National Institutes of Health [AI95921]
Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo(1). Reduced suppressive function and/or number of peripheral T-reg cells has been previously reported in autoimmune disorders(2,3). 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(4,5). 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.
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