Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells

J Exp Med. 2000 Mar 20;191(6):985-94. doi: 10.1084/jem.191.6.985.

Abstract

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase-signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3- and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Ctheta was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Carrier Proteins / biosynthesis
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokines / physiology*
  • DNA-Binding Proteins*
  • Enzyme Activation / immunology
  • Gene Expression Regulation / immunology
  • Genes, Immediate-Early / immunology
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology*
  • Isoenzymes / metabolism
  • Lymphocyte Activation* / genetics
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Biosynthesis
  • Protein Kinase C / metabolism
  • Protein Kinase C-theta
  • Receptors, Antigen, T-Cell / physiology*
  • Repressor Proteins*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators*
  • Transcription Factors*
  • src Homology Domains / genetics
  • src Homology Domains / physiology*

Substances

  • Carrier Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Isoenzymes
  • Receptors, Antigen, T-Cell
  • Repressor Proteins
  • Socs1 protein, mouse
  • Socs2 protein, mouse
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • cytokine inducible SH2-containing protein
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta
  • Mitogen-Activated Protein Kinases