title: 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: 1] Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy. [2] Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy. [3].
authors: Fortunata
authors: F
authors: Carbone
authors: 1] Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy. [2] Unità di NeuroImmunologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Roma, Italy. [3].
authors: Veronica
authors: V
authors: De Rosa
authors: Dipartimento di Neuroscienze, Università di Napoli Federico II, Napoli, Italy.
authors: Pietro B
authors: PB
authors: Carrieri
authors: Dipartimento di Neuroscienze, Università di Napoli Federico II, Napoli, Italy.
authors: Silvana
authors: S
authors: Montella
authors: Dipartimento di Scienze Mediche Preventive, Università di Napoli Federico II, Napoli, Italy.
authors: Dario
authors: 0000000199114646
authors: D
authors: Bruzzese
authors: Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli Federico II, Napoli, Italy.
authors: Antonio
authors: A
authors: Porcellini
authors: 1] Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy. [2] Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.
authors: Claudio
authors: C
authors: Procaccini
authors: Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
authors: Antonio
authors: A
authors: La Cava
authors: 1] Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy. [2] IRCCS MultiMedica, Milano, Italy.
authors: Giuseppe
authors: G
authors: Matarese
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27