Journal
CELL CYCLE
Volume 14, Issue 21, Pages 3362-3372Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1093703
Keywords
differentiation; human; IL-12; IL-21; poly-functional CD4(+) T cells
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Funding
- National Science Foundation of China [31470888]
- Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology [2013A061401007]
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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-. However, the effects of IL-12 on regulating generation of human IL-21- and IFN--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- with or without IL-2 and TNF-. At early stage of differentiation, addition of excess exogenous IFN- could increase the generation of IL-21- and IFN--expressing CD4(+) T cells, furthermore, anti-IFN- depressed the percentage of poly-functional CD4(+) T cells. Phenotypically, IL-21(+)IFN-(+)CD4(+) T cells exhibited more characteristic features about both of Th1 and Tfh cells than IL-21 or IFN- single-expressing CD4(+) T cells. Mechamistically, IL-12 modulated the differentiation of IL-21(+)IFN-(+)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-(+)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.
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