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

Area of Science:

• Immunology
• Allergy Research
• Molecular Biology

Background:

• Pathogenic T helper 2 (T_H2) cells drive allergic disorders like asthma by producing IL-5 and IL-13.
• Thymic stromal lymphopoietin (TSLP) is a key cytokine that stimulates these pathogenic T_H2 cell responses.

Purpose of the Study:

• To investigate the molecular mechanisms by which TSLP and IL-4 induce pathogenic T_H2 cell responses.
• To explore the role of TSLP signaling in allergic disease models and human samples.

Main Methods:

• Analysis of transcriptional changes in mouse CD4+ T cells upon TSLP and IL-4 stimulation.
• Assessment of cytokine production and pathogenic phenotypes of programmed T_H2 cells.
• In vivo studies using mouse models of house dust mite allergy.
• Evaluation of TSLP and IL-4 effects on human CD4+ T cells and peripheral blood from asthmatic children.

Main Results:

• TSLP signaling in mouse CD4+ T cells initiated T_H2 cell programming, which was amplified and stabilized by IL-4.
• TSLP- and IL-4-programmed T_H2 cells exhibited a pathogenic phenotype with increased IL-5 and IL-13 production.
• TSLP-mediated induction involved JAK2/STAT5 activation and BCL6 repression.
• Mice receiving TSLP receptor-deficient T cells showed reduced allergic responses.
• Transient TSLP signaling led to stable pathogenic potential in memory T_H2 cells.
• In humans, TSLP and IL-4 promoted IL-5 and IL-13 producing T_H2 cells, with enhanced responses in asthmatic children.

Conclusions:

• TSLP and IL-4 act sequentially to stably program pathogenic T_H2 cells.
• Distinct molecular pathways mediate TSLP-driven T_H2 cell induction.
• This study provides a mechanistic basis for targeting TSLP signaling in allergic diseases.