A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production.
Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3(+/-) mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon gamma and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.
Matsumoto
Akira
A
Research Institute for Biological Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
Seki
Yoh-ichi
Y
Watanabe
Ryosuke
R
Hayashi
Katsuhiko
K
Johnston
James A
JA
Harada
Yohsuke
Y
Abe
Ryo
R
Yoshimura
Akihiko
A
Kubo
Masato
M
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D018106:CD28 Antigens; D007376:Interleukin-2; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D015847:Interleukin-4; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases