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 language | English |
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Pages (from-to) | 69-74 |
Number of pages | 6 |
Journal | Nature Medicine |
Volume | 20 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2014 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)