Abstract
Patients with Wiskott-Aldrich syndrome (WAS) have numerous immune cell deficiencies, but it remains unclear how abnormalities in individual cell types contribute to the pathologies of WAS. In T cells, the WAS protein (WASp) regulates actin polymerization and transcription, and plays a role in the dynamics of the immunologic synapse. To examine how these events influence CD4 function, we isolated the WASp deficiency to CD4(+) T cells by adoptive transfer into wild-type mice to study T-cell priming and effector function. WAS(-/-) CD4(+) T cells mediated protective T-helper 1 (Th1) responses to Leishmania major in vivo, but were unable to support Th2 immunity to Nippostrongylus brasiliensis or L major. Mechanistically, WASp was not required for Th2 programming but was required for Th2 effector function. WAS(-/-) CD4(+) T cells up-regulated IL-4 and GATA3 mRNA and secreted IL-4 protein during Th2 differentiation. In contrast, cytokine transcription was uncoupled from protein production in WAS(-/-) Th2-primed effectors. WAS(-/-) Th2s failed to produce IL-4 protein on restimulation despite elevated IL-4/GATA3 mRNA. Moreover, dominant-negative WASp expression in WT effector T cells blocked IL-4 production, but had no effect on IFNgamma. Thus WASp plays a selective, posttranscriptional role in Th2 effector function.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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GATA3 Transcription Factor / biosynthesis
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / immunology
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Humans
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Leishmania major / immunology
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Leishmaniasis, Cutaneous / genetics
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Leishmaniasis, Cutaneous / immunology
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Leishmaniasis, Cutaneous / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nippostrongylus / immunology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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Strongylida Infections / genetics
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Strongylida Infections / immunology
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Strongylida Infections / metabolism
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Th1 Cells / immunology
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Transcription, Genetic / genetics
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Transcription, Genetic / immunology
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Up-Regulation / genetics
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Up-Regulation / immunology
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Wiskott-Aldrich Syndrome / genetics
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Wiskott-Aldrich Syndrome / immunology
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Wiskott-Aldrich Syndrome / metabolism
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Wiskott-Aldrich Syndrome Protein / genetics
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Wiskott-Aldrich Syndrome Protein / immunology*
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Wiskott-Aldrich Syndrome Protein / metabolism
Substances
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GATA3 Transcription Factor
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Gata3 protein, mouse
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RNA, Messenger
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Was protein, mouse
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Wiskott-Aldrich Syndrome Protein
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Interleukin-4
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Interferon-gamma