Cytotoxic T-lymphocyte antigen-4 inhibits GATA-3 but not T-bet mRNA expression during T helper cell differentiation.
Naive CD4+ T-cell differentiation to T helper 1 (Th1) and Th2 cells is dependent on T-bet and GATA-3 factors, respectively. T-bet and GATA-3, indeed, through chromatin remodelling allow transcriptional activation of Ifngamma and Th2 cytokine (Il4, Il5, Il13) genes, respectively. We investigated the effects of the negative costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) on GATA-3 and T-bet mRNA expression and Th cell differentiation in mouse naive CD4+ T cells. Our results show that CTLA-4 inhibits GATA-3 mRNA expression and Th2 cell differentiation. At variance, CTLA-4 does not affect T-bet mRNA expression and Th1 cell differentiation. GATA-3 mRNA expression is inhibited when CD4+ cells are stimulated under both neutral (i.e. absence of cytokines) and Th2-polarizing (i.e. presence of interleukin (IL)-4) conditions, the effect being larger under the latter condition. Hence CTLA-4 might affect the IL-4/signal transducer and activator of transcription-6 (STAT6) pathway leading to GATA-3 mRNA up-regulation. We found, indeed, that CTLA-4 engagement inhibits STAT6 activation leaving unaffected the STAT6 protein level. Moreover, CTLA-4 engagement drastically inhibits IL-4Ralpha mRNA and protein up-regulation under Th2-polarizing conditions. Thus, CTLA-4 exerts a tight control on Th2 cell differentiation by negatively regulating both the CD3/CD28 and the IL-4/STAT6 pathways.
Nasta
Francesca
F
ENEA, Unit of Biotechnology, Section of Toxicology and Biomedicine, Rome, Italy.
Ubaldi
Vanessa
V
Pace
Luigia
L
Doria
Gino
G
Pioli
Claudio
C
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050800:STAT6 Transcription Factor / Q000378:metabolism; D020825:T-Box Domain Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000098815:T-bet Transcription Factor; D053662:Interleukin-4 Receptor alpha Subunit
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D050990:GATA3 Transcription Factor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; C556707:Ctla4 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit