Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27.
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(DeltaLck/DeltaLck) 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 Socs3(DeltaLck/DeltaLck) T cells, and T cells from gp130(Y757F/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 Socs3(DeltaLck/DeltaLck) 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.
Brender
Christine
C
Signal Transduction Laboratory, St Vincent's Institute, Fitzroy, Victoria, Australia.
Tannahill
Gillian M
GM
Jenkins
Brendan J
BJ
Fletcher
Joel
J
Columbus
Ruth
R
Saris
Christiaan J M
CJ
Ernst
Matthias
M
Nicola
Nicos A
NA
Hilton
Douglas J
DJ
Alexander
Warren S
WS
Starr
Robyn
R
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015850:Interleukin-6 / Q000096:biosynthesis*; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D018106:CD28 Antigens; C486767:Il27 protein, mouse; D015850:Interleukin-6; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D014443:Tyrosine