TSLP

Official Full Name

thymic stromal lymphopoietin

Organism

Homo sapiens

GeneID

85480

Background

This gene encodes a hemopoietic cytokine proposed to signal through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor and the IL-7R alpha chain. It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells. The protein promotes T helper type 2 (TH2) cell responses that are associated with immunity in various inflammatory diseases, including asthma, allergic inflammation and chronic obstructive pulmonary disease. The protein is therefore considered a potential therapeutic target for the treatment of such diseases. In addition, the shorter (predominant) isoform is an antimicrobial protein, displaying antibacterial and antifungal activity against B. cereus, E. coli, E. faecalis, S. mitis, S. epidermidis, and C. albicans. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2020]

Synonyms

TSLP; Thymic Stromal Lymphopoietin; Thymic stromal lymphopoietin Precursor;

Protein Sequence

MFPFALLYVLSVSFRKIFILQLVGLVLTYDFTNCDFEKIKAAYLSTISKDLITYMSGTKSTEFNNTVSCSNRPHCLTEIQSLTFNPTAGCASLAKEMFAMKTKAALAIWCPGYSETQINATQAMKKRRKRKVTTNKCLEQVSQLQGLWRRFNRPLLKQQ

Open

Disease

Asthma, Atopic eczema, Chronic obstructive pulmonary disease

Approved Drug

1 +

Clinical Trial Drug

6 +

Discontinued Drug

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Detailed Information

Thymic Stromal Lymphopoietin (TSLP) is encoded by a gene located on human chromosome 5q22.1 and belongs to the four-helix bundle cytokine family. The gene produces two primary isoforms through alternative splicing: a long form (TSLPL, 159 amino acids) and a short form (TSLPS, 60 amino acids). These isoforms are controlled by distinct promoters and serve different biological functions. The long isoform is mainly expressed in epithelial cells of barrier tissues such as the lung, skin, and intestine, acting as a critical initiator of inflammatory responses. In contrast, the short isoform is constitutively expressed across multiple tissues, contributing to immune homeostasis and exhibiting direct antimicrobial activity. Structurally, TSLPL shares approximately 43% homology with interleukin-7 (IL-7) and signals through a heterodimeric receptor composed of the TSLP-specific receptor (TSLPR, encoded by the CRLF2 gene) and the IL-7 receptor α chain (IL-7Rα).

Figure 1. TSLP Acts Across the Spectrum of Asthma Inflammation. (Parnes JR, et al., 2022)

TSLP signaling is tightly regulated. Upon binding to its receptor complex, it activates the JAK1 and JAK2 kinases, which in turn phosphorylate and activate transcription factors such as STAT5 and STAT3, while also engaging the MAPK and NF-κB pathways. This multi-pathway activation allows TSLP to influence gene expression in diverse immune cells, including dendritic cells, T cells, mast cells, eosinophils, and type 2 innate lymphoid cells (ILC2s). TSLP expression is strongly regulated by the tissue microenvironment: Toll-like receptor ligands, pro-inflammatory cytokines, and specific cytokine combinations can induce epithelial cells to release the long isoform, initiating inflammatory cascades. Evolutionarily, TSLP is highly conserved in mammals but exhibits functional differences across species, with humans showing a pronounced type 2 immune bias while mice participate in both type 1 and type 2 responses. These species-specific differences are critical considerations in translational research and help explain why some TSLP-targeted therapies show strong preclinical effects but less predictable clinical outcomes.

Biological Functions and Pathological Implications

TSLP acts as an epithelial-derived alarmin, playing a central role in immune surveillance at barrier tissues such as the respiratory tract, skin, and gut. Under normal conditions, the short isoform exerts antimicrobial effects via its cationic C-terminal domain, directly killing Gram-positive bacteria and fungi and forming a chemical barrier on mucosal surfaces. When tissues encounter allergens, pathogens, or mechanical injury, epithelial cells rapidly release the long isoform, triggering complex immune cascades. A key mechanism involves TSLP-induced expression of OX40 ligand on dendritic cells, promoting the differentiation of naïve CD4⁺ T cells into Th2 cells and the production of type 2 cytokines such as IL-4, IL-5, and IL-13.

In asthma, TSLP-driven Th2 responses contribute to IgE synthesis, mast cell activation, mucus overproduction, and airway hyperreactivity. TSLP also interacts with progenitor cells expressing TSLPR, supporting their differentiation into mature eosinophils and sustaining eosinophilic inflammation.

TSLP exhibits a dual, context-dependent role in tumors. In breast cancer, tumor cells can induce TSLP expression in infiltrating immune cells, which then activates anti-apoptotic pathways within cancer cells, enhancing survival. Blocking TSLP or genetically deleting it in preclinical models reduces tumor growth and metastasis while promoting apoptosis. This effect has been observed in multiple cancers, including pancreatic, cervical, and multiple myeloma. Interestingly, in some early-stage cancers such as esophageal squamous cell carcinoma, high TSLP expression correlates with better prognosis, suggesting its role in anti-tumor immune activation may depend on tumor stage, microenvironment composition, and timing.

TSLP plays a central role in inflammatory diseases by bypassing traditional Th2 pathways and directly activating memory CD4⁺ T cells and ILC2s. In severe asthma, TSLP contributes to steroid resistance by maintaining ILC2 survival and promoting ongoing production of IL-5 and IL-13, highlighting its potential as a therapeutic target.

Figure 2. TSLP: environmental inducers, cellular sources and its variety of targets and actions. (Smolinska S, et al., 2023)

Therapeutic Progress and Clinical Prospects

Monoclonal antibodies targeting TSLP represent a major advance in asthma therapy. Tezepelumab, a fully human IgG2λ antibody, inhibits the interaction between TSLP and TSLPR, suppressing downstream inflammatory signaling. Clinical studies show it reduces exacerbations, improves lung function, and broadly suppresses type 2 inflammation markers, offering treatment options for patients with complex asthma phenotypes, including those with low eosinophil counts. Other TSLP-targeted therapies are also under development, including inhaled antibodies designed to limit systemic exposure.

Beyond asthma, TSLP inhibition shows promise in other inflammatory conditions, such as atopic dermatitis and COPD, where it reduces immune cell infiltration and improves tissue function. In cancer therapy, TSLP blockade may enhance anti-tumor immunity by reducing immunosuppressive cells and activating cytotoxic T cells. Early-phase trials are exploring combinations of TSLP inhibitors with immune checkpoint therapies in solid tumors, indicating potential expansion of therapeutic indications.

Reference

Parnes JR, Molfino NA, Colice G, et al. Targeting TSLP in Asthma. J Asthma Allergy. 2022 Jun 3;15:749-765.
Smolinska S, Antolín-Amérigo D, Popescu FD, et al. Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma. Int J Mol Sci. 2023 Aug 12;24(16):12725.

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