Suppressor of Cytokine Signaling 3 Regulates Proliferation and Activation of T-helper Cells

• Published in: The Journal of biological chemistry 2003-08, Vol.278 (32), p.29752-29759
• Main Authors: Yu, Cheng-Rong, Mahdi, Rashid M., Ebong, Samuel, Vistica, Barbara P., Gery, Igal, Egwuagu, Charles E.
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Northern; Blotting, Western; Carrier Proteins - metabolism; Cell Division; Cytokines - metabolism; DNA, Complementary - metabolism; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Genes, Reporter; Interleukin-2 - metabolism; Lymphocyte Activation; Mice; Mice, Transgenic; Oligonucleotides, Antisense - metabolism; Proteins - metabolism; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - physiology; Time Factors; Trans-Activators; Transcription Factors; Transcription, Genetic; Transfection; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M300489200

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 cytokineinduced 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.