期刊
SCIENCE SIGNALING
卷 11, 期 521, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aam8858
关键词
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资金
- Cincinnati Children's Research Foundation
- University Research Council (URC) - University of Cincinnati
- Center for Clinical and Translational Science and Training (CCTST)
- CCTST [Clinical and Translational Science Award (CTSA) [1UL1TR001425-01]
- Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH
- NIH [AR-47363, DK78392, DK90971, R01 HL122300]
Pathogenic T helper 2 (T(H)2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic T(H)2 cell responses. We found that TSLP signaling in mouse CD4(+) T cells initiated transcriptional changes associated with T(H)2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13. Furthermore, the TSLP-and IL-4-programmed T(H)2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did T(H)2 cells stimulated with IL-4 alone. TSLP-mediated T(H)2 cell induction involved distinct molecular pathways, including activation of the transcription factor STAT5 through the kinase JAK2 and repression of the transcription factor BCL6. Mice that received wild-type CD4(+) T cells had exacerbated pathogenic T(H)2 cell responses upon exposure to house dust mites compared to mice that received TSLP receptor-deficient CD4(+) T cells. Transient TSLP signaling stably programmed pathogenic potential in memory T(H)2 cells. In human CD4(+) T cells, TSLP and IL-4 promoted the generation of T(H)2 cells that produced greater amounts of IL-5 and IL-13. Compared to healthy controls, asthmatic children showed enhancement of such T cell responses in peripheral blood. Our data support a sequential cytokine model for pathogenic T(H)2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.
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