title: Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott-Aldrich syndrome patients.
abstract: Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4+ and CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-gamma, and TNF-alpha are strongly reduced in CD8+ T cells from WAS patients, compared with healthy donor CD8+ T cells. Furthermore, WAS CD4+ T cells secrete low levels of IL-2 and fail to produce IFN-gamma and TNF-alpha, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-gamma production persists after culture of naive WAS CD4+ T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4+ and CD8+ T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN-gamma mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4+ T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8+ T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Trifari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Francesco
authors.initials: F
authors.lastname: Marangoni
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Paola
authors.initials: P
authors.lastname: Saracco
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors