In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 11, No. 521 ( 2018-03-13)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.aam8858
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2018
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