title: IL-12 induced the generation of IL-21- and IFN-γ-co-expressing poly-functional CD4+ T cells from human naive CD4+ T cells.
abstract: Interleukine-12 is critical for the differentiation of Th1 cells and can improve the development of Th1 cells with Tfh cell features in mouse model. Human effector CD4(+) T cells also exhibit poly-functionality by co-expressing IL-21 and IFN-γ. However, the effects of IL-12 on regulating generation of human IL-21- and IFN-γ-expressing CD4(+) T cells are still incompletely understood. Our studies found that IL-12 but not IL-21 could induce the differentiation of human naive CD4(+) T cells into multi-cytokine expressing CD4(+) T cells in vitro, which co-expressed IL-21 and IFN-γ with or without IL-2 and TNF-α. At early stage of differentiation, addition of excess exogenous IFN-γ could increase the generation of IL-21- and IFN-γ-expressing CD4(+) T cells, furthermore, anti-IFN-γ depressed the percentage of poly-functional CD4(+) T cells. Phenotypically, IL-21(+)IFN-γ(+)CD4(+) T cells exhibited more characteristic features about both of Th1 and Tfh cells than IL-21 or IFN-γ single-expressing CD4(+) T cells. Mechamistically, IL-12 modulated the differentiation of IL-21(+)IFN-γ(+)CD4(+) T cells from naive CD4(+) T cells via the pathways of STAT-1/4, T-bet and BCL(-)6. Different from naive CD4(+) T cells, IL-12 increasing the generation of IL-21(+)IFN-γ(+)CD4(+) T cells from memory CD4(+) T cells was only involved in STAT-4 pathway but not STAT-1. Poly-functional CD4(+) T cells were contributed to generation and progress of varies diseases and our studies provide basic theoretics for the designs of vaccine and therapies of diseases.
authors.affiliation: a Institute of Immunology; Zhongshan School of Medicine; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Sifei
authors.initials: S
authors.lastname: Yu
authors.affiliation: a Institute of Immunology; Zhongshan School of Medicine; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.affiliation: a Institute of Immunology; Zhongshan School of Medicine; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Guangzhou Women and Children's Medical Center ; Guangzhou , China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: a Institute of Immunology; Zhongshan School of Medicine; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Binyan
authors.initials: B
authors.lastname: Yang
authors.affiliation: a Institute of Immunology; Zhongshan School of Medicine; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Wu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007156:Immunologic Memory; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D010641:Phenotype; D051560:Proto-Oncogene Proteins c-bcl-6; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C573415:IFNG protein, human; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: IL-12; IL-21; differentiation; human; poly-functional CD4+ T cells