Negative Regulation of Cytokine Signaling in Immunity

Abstract

Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4⁺ T cells and the maturation of CD8⁺ T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity.

Figure 1.

The cytokine signaling and their major negative regulators. There are four types of cytokine receptors: (1) receptors that activate nuclear factor (NF)-κB and mitogen-activated protein (MAP) kinases; (2) receptors that activate the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway; (3) transforming growth factor (TGF)-β receptors; and (4) growth factor receptor family. Typical negative regulators are also shown. TNF, Tumor necrosis factor; TNFR, TNF receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; IKK, IκB kinase; SOCS/CIS, suppressor of cytokine signaling/cytokine-inducible Src homology 2 (SH2)-containing protein; Spred, Sprouty-related protein with an EVH1 domain.

Figure 2.

Structure and function of the suppressor of cytokine signaling (SOCS) family. The SOCS family consists of eight family members. All eight members share a central Src homology 2 (SH2) domain and a carboxy-terminal SOCS box. In addition, SOCS1 and SOCS3 possess a kinase inhibitory region (KIR) that inhibits Janus kinase (JAK) activity. (Right) The general mechanism of the action of cytokine-inducible SH2-containing protein (CIS), SOCS1, and SOCS3. STAT, Signal transducers and activators of transcription; JAB, Janus kinase-binding protein.

Figure 3.

Structure of the complex of Janus kinase (JAK)2 and suppressor of cytokine signaling (SOCS)3, and gp130 phosphopeptide. SOCS3 binds the kinase domains of JAK1, JAK2, and TYK2 and inhibits its catalytic activity by blocking the substrate-binding site with its kinase inhibitory region. SOCS3 remains bound to gp130 while in complex with JAK (beige) and adenosine triphosphate (ATP) binding is unaffected. (Based on Kershaw et al. 2013, with permission, from the authors.)