Research ArticleImmunology

TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state

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Sci. Signal.  13 Mar 2018:
Vol. 11, Issue 521, eaam8858
DOI: 10.1126/scisignal.aam8858

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TSLP as a therapeutic target

Although T helper 2 (TH2) cells mediate immunity against extracellular parasites, they also promote allergic inflammation. The cytokine interleukin-4 (IL-4), which is produced by TH2 cells, is also required for their differentiation. Noting that the cytokine TSLP is implicated in the pathogenesis of TH2 cell–associated allergic disorders, Rochman et al. investigated its role in TH2 cell differentiation. They found that TH2 cells that differentiated in the presence of TSLP and IL-4 produced increased amounts of cytokines and were more pathogenic compared to TH2 cells differentiated in the presence of IL-4 alone. Mice that received CD4+ T cells deficient in the TSLP receptor had reduced allergic responses compared to those that received wild-type cells. Given that pediatric asthma patients had enhanced TH2 cytokine production compared to that of healthy controls, these data suggest that TSLP may be a therapeutic target in allergic diseases.

Abstract

Pathogenic T helper 2 (TH2) 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 TH2 cell responses. We found that TSLP signaling in mouse CD4+ T cells initiated transcriptional changes associated with TH2 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 TH2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did TH2 cells stimulated with IL-4 alone. TSLP-mediated TH2 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 TH2 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 TH2 cells. In human CD4+ T cells, TSLP and IL-4 promoted the generation of TH2 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 TH2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.

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