CD28 costimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells.
The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation. Here, we investigated how CD28 costimulation functions to allow TCR-triggered resting T cells to acquire IL-12 responsiveness. When T cells are stimulated with low doses of anti-CD3 mAb, CD28 costimulation was required for the optimal levels of IL-12 receptor (IL-12R) expression. However, stimulation of T cells with high doses of anti-CD3 alone induced comparable levels of IL-12R expression to those induced upon CD28 costimulation. Nevertheless, there was a substantial difference in IL-12 responsiveness between these two groups of T cells: compared to anti-CD28-costimulated T cells, T cells that were not costimulated with anti-CD28 exhibited decreased levels of Janus kinases (JAK) JAK2/TYK2 and STAT4 phosphorylation and IFN-y production following IL-12 stimulation. Importantly, STAT6 phosphorylation following IL-4 stimulation was not decreased in anti-CD28-uncostimulated T cells. These resutls indicate that CD28 costimulation not only contributes to up-regulating IL-12R expression but is also required to render JAKs/STAT4 responsive to IL-12 stimulation.
Park
W R
WR
Department of Oncology, Osaka University Graduate School of Medicine, Suita, Japan.
Park
C S
CS
Tomura
M
M
Ahn
H J
HJ
Nakahira
Y
Y
Iwasaki
M
M
Gao
P
P
Abe
R
R
Hamaoka
T
T
Fujiwara
H
H
D000818:Animals; D015153:Blotting, Western; D018106:CD28 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases