Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice.
Although c-Maf is crucial for Th2 differentiation and production of interleukin 4 (IL-4), its regulation is poorly understood. We report that Vav1-/- CD4+ T cells display deficient T-cell receptor (TCR)/CD28-induced IL-4 and c-Maf expression and, conversely, enhanced interferon gamma (IFN-gamma) production and T-bet expression (even when cultured under Th2-polarizing conditions), but intact expression of other Th2 cytokines and GATA-3. Up-regulation of c-Maf was dependent on Ca2+/nuclear factor of activated T cell (NFAT) and, together with IL-4 production, could be rescued in Vav1-/- T cells by Ca2+ ionophore. Deficient IL-4 production was restored by retrovirus-mediated Vav1 expression, but only partially by retroviral c-Maf expression. Similar IL-4 --> IFN-gamma skewing was observed in intact, antigen-primed Vav1-/- mice. Thus, Vav1 is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression on Ca2+/NFAT signaling.
Tanaka
Yoshihiko
Y
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr, San Diego, CA 92121, USA.
So
Takanori
T
Lebedeva
Svetlana
S
Croft
Michael
M
Altman
Amnon
A
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C495608:Maf protein, mouse; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C496619:Vav1 protein, mouse; D015847:Interleukin-4; D002118:Calcium