Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells

doi:10.1073/pnas.0600666103

Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells

*Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and
^§Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and
^¶Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Edited by James E. Darnell, Jr., The Rockefeller University, New York, NY, and approved April 13, 2006
↵ ^†Z.C. and A.L. contributed equally to this work. (received for review January 25, 2006)

Abstract

Suppressor of cytokine signaling (Socs) 3 is a cytokine-inducible inhibitor with critical but selective cell-specific effects. We show that deficiency of Socs3 in T cells had minimal effects on differentiation of T cells to the T helper (Th) 1 or Th2 subsets; accordingly, Socs3 had no effect on IL-12-dependent signal transducer and activator of transcription (Stat) 4 phosphorylation or IL-4-dependent Stat6 phosphorylation. By contrast, Socs3 was found to be a major regulator of IL-23-mediated Stat3 phosphorylation and Th17 generation, and Stat3 directly binds to the IL-17A and IL-17F promoters. We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation.

Footnotes

^‡To whom correspondence should be addressed at:
National Institutes of Health, Building 10, Room 9N262, 10 Center Drive, MSC-1820, Bethesda, MD 20892-1820.
E-mail: laurencea{at}mail.nih.gov
Author contributions: Z.C., A.L., and J.J.O. designed research; Z.C., A.L., Y.K., M.P.-Z., and B.-M.Z. performed research; A.Y. and L.H. contributed new reagents/analytic tools; Z.C., A.L., Y.K., C.T., and J.J.O. analyzed data; and Z.C., A.L., and J.J.O. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

Socs,

suppressor of cytokine signaling;

Stat,

signal transducer and activator of transcription;

Th,

T helper;

G-CSF,

granulocyte/colony-stimulating factor;

q-PCR,

quantitative PCR.
Freely available online through the PNAS open access option.