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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2528-2536.
Prepublished online as a Blood First Edition Paper on July 3, 2007; DOI 10.1182/blood-2006-08-041541.
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IMMUNOBIOLOGY
Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27
Christine Brender1,
Gillian M. Tannahill1,
Brendan J. Jenkins2,
Joel Fletcher1,
Ruth Columbus3,
Christiaan J. M. Saris4,
Matthias Ernst5,
Nicos A. Nicola3,
Douglas J. Hilton6,
Warren S. Alexander3, and
Robyn Starr1
1 Signal Transduction Laboratory, St Vincent's Institute, Fitzroy, Victoria, Australia;
2 Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;
3 Division of Cancer and Haemotology, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia;
4 Department of Inflammation Research, Amgen, Thousand Oaks, CA;
5 Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia;
6 Molecular Medicine Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia
Suppressor of cytokine signaling (SOCS) proteins regulate the intensity and duration of cytokine responses. SOCS3 is expressed in peripheral T cells, and recent reports have suggested that overexpression of SOCS3 modulates antigen- and/or costimulation-induced T-cell activation. To study the role of SOCS3 in the regulation of T-cell activation, we used a conditional gene-targeting strategy to generate mice that lack SOCS3 in T/natural killer T cells (Socs3 Lck/Lck mice). SOCS3-deficient CD8 T cells showed greater proliferation than wild-type cells in response to T-cell receptor (TCR) ligation despite normal activation of signaling pathways downstream from TCR or CD28 receptors. Signaling in response to the gp130 cytokines interleukin (IL)–6 and IL-27 was prolonged in Socs3Lck/Lck T cells, and T cells from gp130Y757F/Y757F mice, in which the SOCS3-binding site on gp130 is ablated, showed a striking similarity to SOCS3-deficient CD8 T cells. Although the proliferative defect of Socs3Lck/Lck T cells was not rescued in the absence of IL-6, suppression of IL-27 signaling was found to substantially reduce anti-CD3–induced proliferation. We conclude that enhanced responses to TCR ligation by SOCS3-deficient CD8 T cells are not caused by aberrant TCR-signaling pathways but, rather, that increased IL-27 signaling drives unregulated proliferation in the absence of SOCS3.
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