Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells.
Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression.
Fowell
D J
DJ
Department of Medicine, University of California San Francisco 94143, USA.
Shinkai
K
K
Liao
X C
XC
Beebe
A M
AM
Coffman
R L
RL
Littman
D R
DR
Locksley
R M
RM
D000818:Animals; D001692:Biological Transport; D018106:CD28 Antigens / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007476:Ionophores; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D015847:Interleukin-4; D015759:Ionomycin; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase