Autoimmune Diseases Targets

TSLP and TSLPR

TSLP (Thymic Stromal Lymphopoietin) is a member of the four-helix bundle cytokine family and is a distant homolog of IL-7. As the name suggests, TSLP was initially identified in the mouse thymic stromal cell line Z210R, as a factor that promotes the proliferation and development of immature B cells. Subsequently, TSLP was found to function as a co-stimulatory factor for thymic cell proliferation and as a lymphopoietin[1]. Although the homology between human and mouse TSLP is low, with only 43% amino acid sequence identity, they have similar biological functions. Both mouse and human TSLP are predominantly expressed by epithelial cells, with the highest expression levels observed in the lung, skin, and intestine[2].

TSLP receptor (TSLPR), a member of the erythropoietin receptor family, has low affinity for TSLP. When TSLPR binds to IL-7Rα, it not only enhances the binding activity to TSLP but also leads to STAT5 activation, enabling cells to respond to TSLP stimulation and undergo proliferation. Therefore, the functional TSLP receptor is a heterodimeric receptor complex composed of TSLPR and IL-7Rα. Similar to TSLP, TSLPR in humans and mice shares only 39% amino acid similarity. However, its function is conserved among all analyzed species, indicating the conservation of this signaling axis between humans and mice[1].

TSLP and TH2

In allergic inflammation, TSLP can strongly activate DCs (dendritic cells), which subsequently drive the development of naive TH cells into "inflammatory" effector TH2 cells that express classical TH2 cytokines, pro-inflammatory tumor necrosis factor-alpha (TNF-α), and anti-inflammatory IL-10. When stimulated by exogenous antigens such as bacteria, viruses, Toll-like receptor (TLR) agonists, etc., blood TSLP levels rapidly increase, and the concentration of TSLP is positively correlated with Th2 immune response and asthma severity.

TSLP and Diseases

TSLP and allergic reactions

The discovery of the association between allergies and the activity of allergen-specific TH2 cells has led to the crucial hypothesis of the role of TSLP in the development and maintenance of atopic allergic diseases. TSLP, along with other epithelial cell-derived cytokines such as IL-25 and IL-33, plays a critical role in the generation and progression of allergic diseases such as asthma, atopic dermatitis (AD), and food allergies. TSLP was initially found to act on DCs, inducing the expression of OX40L, CD80, and CD86. Activated DCs then promote the differentiation of naive CD4+ T cells into TH2 cells, which secrete IL-4, IL-5, IL-13, and TNF, ultimately leading to allergic responses. TSLP also enhances the release of TH2 cytokines and chemokines from eosinophils, mast cells, and macrophages. In addition to its indirect effects, TSLP can directly act on CD4+ T cells, aiding in their proliferation, differentiation, and response to antigens[3].

TSLP and cancer

New functions of TSLP have been discovered in the induction and progression of various tumors, including solid tumors such as breast, colon, and pancreatic cancers, as well as hematological malignancies like B-cell acute lymphoblastic leukemia (B-ALL). Additionally, TSLP signaling has been shown to have a protective effect against skin-derived tumors, indicating its context-dependent role in tumor biology. Therefore, TSLP has emerged as a potential target for cancer therapy[1].

TSLP in R&D of pharmaceuticals

Tezspire (tezepelumab), developed through a collaboration between AstraZeneca and Amgen, is an anti-TSLP monoclonal antibody medication that can block the activity of TSLP and play a role in the initial cascade of inflammatory reactions. In the treatment of severe asthma, Tezspire is the only biologic therapy without phenotype or biomarker restrictions, which indicates that more severe asthma patients have the opportunity to receive treatment. Clinical data has shown that Tezspire can significantly improve symptoms. In 2022, Tezspire generated sales of up to $174 million. Targeting TSLP for drug research continues to hold great promise.

Beta LifeScience offers a range of products related to TSLP targets, including target proteins and reporter gene cell lines. These products are suitable for various applications such as animal immunology, TSLP-targeted drug screening, functional assessment, and quality control in different stages.

Recommended TSLP Reporter Gene Cell Lines

(1) Monoclonal stable transfected cell lines.

(2) High response amplification.

(3) Cell-based validation of antibody performance.

Reference

[1] Corren, J., & Ziegler, S. F. (2019). TSLP: from allergy to cancer. Nature immunology, 20(12), 1603–1609.

[2] Liu, Y. J., Soumelis, V., Watanabe, N., Ito, T., Wang, Y. H., Malefyt, R.deW., Omori, M., Zhou, B., & Ziegler, S. F. (2007). TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annual review of immunology, 25, 193–219.

[3] Ebina-Shibuya, R., & Leonard, W. J. (2023). Role of thymic stromal lymphopoietin in allergy and beyond. Nature reviews. Immunology, 23(1), 24–37.

[4] Kapsenberg M. (2006). Tweaking of memory T helper 2 cells by TSLP. Immunity, 24(6), 673–675.