A mandatory role for STAT4 in IL-12 induction of mouse T cell CCR5.
IL-12 was recently shown to induce CCR5 on TCR-triggered mouse T cells. Considering that STAT4 is the most critical of IL-12 signaling molecules, this study investigated the role for STAT4 in the induction of CCR5 expression. IL-12R was induced by stimulation with anti-CD3 plus anti-CD28 mAb similarly on T cells from wild-type (WT) and STAT4-deficient (STAT4(-/-)) mice, but the levels of IL-12R induced on IFN-gamma-deficient (IFN-gamma(-/-)) T cells were lower compared with WT T cells. Exposure of TCR-triggered WT T cells to IL-12 induced CCR5 expression. In contrast, TCR-triggered STAT4(-/-) T cells failed to express CCR5 in response to IL-12. IL-12 stimulation induced detectable albeit reduced levels of CCR5 expression on IFN-gamma(-/-) T cells. Addition of rIFN-gamma to cultures of IFN-gamma(-/-) T cells, particularly to cultures during TCR triggering resulted in restoration of CCR5 expression. However, CCR5 expression was not induced in STAT4(-/-) T cells by supplementation of rIFN-gamma. These results indicate that for the induction of CCR5 on T cells, 1) STAT4 plays an indispensable role; 2) such a role is not substituted by simply supplementing rIFN-gamma; and 3) IFN-gamma amplifies CCR5 induction depending on the presence of STAT4.
Iwasaki
M
M
Department of Oncology (C6), Osaka University Graduate School of Medicine, Osaka, Japan.
Mukai
T
T
Nakajima
C
C
Yang
Y F
YF
Gao
P
P
Yamaguchi
N
N
Tomura
M
M
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D019713:Receptors, CCR5; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma