title: Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells.
abstract: Suppressors of cytokine signaling (SOCS) have been implicated in regulation of T-cell activation and cytokine-mediated differentiation of T-helper cells. In this study we have characterized the pattern of SOCS expression in naïve and activated primary T-helper cells, examined whether expression of SOCS genes is regulated by cytokine or T-cell receptor signaling, and analyzed the function of SOCS in differentiated T-cells. We show that SOCS1, SOCS2, SOCS3, CIS (cytokine-induced SH2 protein) genes are constitutively expressed in naïve T-helper cells, with SOCS3 being the most abundant. Antigen stimulation of naïve T-helper cells down-regulates SOCS3 expression and concomitantly up-regulates SOCS1, SOCS2, and CIS gene transcription, suggesting that SOCS genes are regulated differentially by T-cell activation. Down-regulation of SOCS3 expression is subsequently followed by gradual increase in SOCS3 level and corresponding decline in interleukin 2 (IL-2) secretion. In fact, SOCS3 mRNA levels are inversely correlated with the amount of IL-2 secretion and proliferative responses of differentiating T-helper cells, suggesting mutually antagonistic effects of SOCS3 and IL-2 and feedback regulation of T-cell activation by SOCS3. Furthermore, the degree of SOCS3 inhibition is antigen concentration-dependent and is mediated in part by growth factor independence-1, a T-cell transcription factor that regulates S-phase entry in T-cells. Forced overexpression of SOCS3 inhibits proliferation of T-helper cells, whereas depletion of endogenous SOCS3 by antisense SOCS3 cDNA enhances T-cell receptor- and cytokine-induced proliferation. Taken together, these results suggest a role for SOCS3 in maintaining T-helper cells in a quiescent state. Transient inhibition of SOCS3 by antigen stimulation may therefore be essential in allowing activation of resting T-cells.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Mahdi
authors.forename: Samuel
authors.initials: S
authors.lastname: Ebong
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Vistica
authors.forename: Igal
authors.initials: I
authors.lastname: Gery
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017930:Genes, Reporter; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors