WSX-1 over-expression in CD4(+) T cells leads to hyperproliferation and cytokine hyperproduction in response to TCR stimulation.
WSX-1 is a component of the IL-27R. Analyses of WSX-1 knockout (WSX-1(-/-)) mice have shown that IL-27/WSX-1 signaling is essential for the proper development of T(h)1 responses and that WSX-1 can suppress cellular activation and pro-inflammatory cytokine production. We have generated transgenic mouse lines over-expressing the WSX-1 gene under the control of the T cell-specific CD2 promoter (WSX-1 Tg mice). Unexpectedly, like activated CD4(+) T cells from WSX-1(-/-) mice, activated CD4(+) T cells from WSX-1 Tg mice showed increased proliferation, augmented IL-2 production and up-regulated surface expression of activation markers. IL-27-mediated tyrosine phosphorylation of STAT1 was also enhanced in WSX-1 Tg CD4(+) T cells, but STAT3 activation was normal. Exogenous IL-27 supported the proliferation of wild-type CD4(+) T cells but suppressed that of WSX-1 Tg cells. WSX-1 over-expression increased IFN-gamma production in T(h)1-polarized CD4(+) T cells, but also promoted T(h)2 cytokine production under T(h)1-polarizing conditions. Importantly, WSX-1 over-expression failed to suppress T(h)2 cytokine production under T(h)2-polarizing conditions. Cytokine hyperproduction was also observed in vivo in WSX-1 Tg mice injected with Con A. Our data suggest that WSX-1 plays a pivotal role in regulating T cell responsiveness to TCR stimulation and that the correct balance of STAT1/STAT3 activation downstream of IL-27R engagement is crucial for the physiological function of IL-27.
Takeda
Atsunobu
A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Hamano
Shinjiro
S
Shiraishi
Hiroshi
H
Yoshimura
Takeru
T
Ogata
Hisanobu
H
Ishii
Kazunari
K
Ishibashi
Tatsuro
T
Yoshimura
Akihiko
A
Yoshida
Hiroki
H
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis*; D007378:Interleukins / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D018801:CD2 Antigens; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D003208:Concanavalin A