Regulatory T cell proliferative potential is impaired in human autoimmune disease.

Abstract

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.

• Authors: Fortunata Carbone, Veronica De Rosa, Pietro B Carrieri, Silvana Montella, Dario Bruzzese, Antonio Porcellini, Claudio Procaccini, Antonio La Cava, Giuseppe Matarese
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 1 Pg. 69-74 (Jan 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 24317118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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)