TSLP

MEDIUM

Thymic Stromal Lymphopoietin

Chromosome: 5q22.1

Gene Overview

TSLP encodes thymic stromal lymphopoietin, an epithelial-derived cytokine (alarmin) that plays a central role in initiating and amplifying type 2 immune responses. TSLP is produced by epithelial cells in the skin, airways, and gut in response to environmental triggers including allergens, particulate matter, tobacco smoke, and microbial products. Upon release, TSLP activates dendritic cells via the TSLP receptor (TSLPR/CRLF2) and IL-7Rα heterodimer, priming them to drive naive T cells toward a Th2 phenotype. TSLP also directly activates ILC2s, mast cells, and basophils. GWAS have identified variants at the TSLP locus (5q22.1) associated with asthma, atopic dermatitis, and eosinophilic esophagitis. The anti-TSLP monoclonal antibody tezepelumab has demonstrated clinical efficacy in severe asthma, validating TSLP as a therapeutic target. TSLP expression is regulated by NF-κB and AP-1, and is enhanced by oxidative stress and protease-activated receptor signaling.

Molecular Function

  • epithelial alarmin signaling
  • Th2 immune cascade initiation
  • dendritic cell activation

Protein class: cytokine

Regulatory Annotation

Promoter activity: TSLP promoter contains NF-κB, AP-1, and NFAT binding sites; activated by TLR3 signaling, TNF-α, IL-1β, and protease-activated receptor 2 (PAR2) stimulation.

Enhancer associations: Asthma-associated SNPs (e.g., rs1837253) located 5' of TSLP influence transcription; risk alleles correlate with increased TSLP expression in nasal and bronchial epithelium.

Methylation sensitivity: TSLP promoter methylation inversely correlates with gene expression in atopic dermatitis skin biopsies.

eQTL tissues: skin, bronchial epithelium, lung

Tissue Expression Context

skin epitheliumTPM range: 12–50GTEx vv8
bronchial epitheliumTPM range: 5–25GTEx vv8
thymusTPM range: 3–15GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

TSLP variants modulate the magnitude of epithelial alarm signaling in response to environmental irritants, setting the threshold for type 2 immune cascade initiation. Individuals carrying risk alleles at rs1837253 express higher baseline TSLP in barrier tissues, leading to enhanced dendritic cell priming and Th2 polarization upon exposure to particulate matter or tobacco smoke.

Torgerson et al. identified TSLP variants associated with asthma across multiple ethnic groups; He et al. showed TSLP is essential for Th2 differentiation in response to inhaled antigens; tezepelumab clinical trials confirm TSLP blockade reduces exacerbations independent of baseline eosinophil counts.

MEDIUM

Confidence Rating

Overall evidence confidence for this gene entry: MEDIUM

Ancestry Context

Allele frequencies may vary across ancestries. Effect estimates derived primarily from European-ancestry cohorts.

Cross-ancestry eQTL replication: Unknown

References

  1. 1.Torgerson DG, et al. (2011). Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nature Genetics. doi:10.1038/ng.888
  2. 2.He R, et al. (2009). TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2009.05.018
  3. 3.Ying S, et al. (2005). TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Journal of Immunology. doi:10.4049/jimmunol.175.12.8051