A role for the atopy-associated gene PHF11 in T-cell activation and viability.
Polymorphisms within plant homeodomain finger protein 11 (PHF11) are associated with total IgE, allergic asthma and eczema. PHF11 is a transcriptional co-activator of the Th1 effector cytokine genes, interleukin-2 (IL2) and interferon-γ (IFNG), co-operating with nuclear factor kappa B (NF-κB). The involvement with NF-κB led us to test whether PHF11 might have a broader function in T-cell activation and viability. We show that PHF11 is abundant in the cytoplasm of T-cells and imported into the nucleus of activated T-cells. Consistent with its presence in the nucleus, PHF11 was recruited to the IFNG promoter and over-expression of PHF11 increased the binding of NF-κB to the IFNG promoter and IFNG gene transcription. Over-expression of PHF11 did not increase IL2 gene transcription, suggesting some specificity in promoter recognition. In contrast, small-interfering RNA knock-down of PHF11 decreased transcription of both IFNG and IL2 and led to decreased CD28 cell-surface expression and reduced NF-κB nuclear import and DNA binding. Knock-down of PHF11 also decreased cell viability and was accompanied by reduced expression of GIMAP4 and 5 genes required for T-cell differentiation, viability and homeostasis. Therefore, in addition to its earlier identified function in regulating Th1 cytokine gene expression, we now show that PHF11 has a broader function in contributing to T-cell activation and viability.
Rahman
Nusrat
N
Department of Immunology and Allergy Research, Westmead Millennium Institute, Westmead Hospital, The University of Sydney, New South Wales, Australia.
Stewart
Graeme
G
Jones
Graham
G
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016328:NF-kappa B; C493258:PHF11 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D007371:Interferon-gamma