Role of thymic stromal lymphopoietin in allergy and beyond

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.

Fig. 1. Inducers, sources and targets of thymic stromal lymphopoietin.

A variety of environmental agents, including mechanical injury, ligands for Toll-like receptors (TLRs), viruses and cytokines, induce the production of thymic stromal lymphopoietin (TSLP). Epithelial cells are the main source of TSLP production. Fibroblasts, dendritic cells (DCs), basophils and mast cells also produce TSLP following stimulation. TSLP has pleiotropic actions on B cells, T cells, eosinophils, group 2 innate lymphoid cells (ILC2s), natural killer T (NKT) cells, macrophages, smooth muscle cells and nerve cells, and it also has effects on DCs, basophils and mast cells. IFNγ, interferon-γ; LCMV, lymphocytic choriomeningitis virus; TNF, tumour necrosis factor; RSV, respiratory syncytial virus.

Fig. 2. Mechanisms of thymic stromal lymphopoietin-induced signalling.

Thymic stromal lymphopoietin (TSLP) binds to a receptor comprising TSLP receptor (TSLPR) and IL-7 receptor α-chain (IL-7Rα), which are both type 1 membrane receptor proteins. TSLP binding activates JAK1, JAK2 and signal transducer and activator of transcription 5A and 5B (STAT5A and STAT5B) to promote the transcription of target genes, including the type 2 cytokines IL-4, IL-5 and IL-9.

Fig. 3. TSLP in allergic diseases and viral infection.

a | The release of thymic stromal lymphopoietin (TSLP) is stimulated by epithelial cell exposure to allergens, microorganisms and chemicals. TSLP promotes and amplifies T helper 2 (T_H2)-type immunity, which enhances the immune response to antigens or allergens through both adaptive and innate immune mechanisms, leading to the development and/or progression of allergic disease. Whether TSLP induces or enhances the production of histamine, IL-4 and IL-13 by basophils requires further investigation. b | Viral infection also triggers the production of TSLP from epithelial cells. TSLP supports the survival of cytotoxic T cells both directly and indirectly through the activation of dendritic cells (DCs); however, the functional role of TSLP during antiviral immune responses is still controversial in influenza virus infection. CCL, CC-chemokine ligand; ECP, eosinophil cationic protein; EDN, eosinophil‑derived neurotoxin; EPX, eosinophil peroxidase; GM-CSF, granulocyte-macrophage colony-stimulating factor; ILC2, group 2 innate lymphoid cell; LAMP, lysosome-associated membrane protein; MBP, major basic protein; NGF, nerve growth factor; TCR, T cell receptor; TGFβ, transforming growth factor-β.

Fig. 4. TSLP in cancer.

a | Thymic stromal lymphopoietin (TSLP) secreted by either cancer-associated fibroblasts or tumour cells has tumour-promoting effects predominantly through the establishment of T helper 2 (T_H2)-type inflammation in the tumour microenvironment, mostly through dendritic cell (DC) activation. T_H2 cells and eosinophils promote angiogenesis through the production of vascular endothelial growth factor (VEGF) and IL-8. b | T_H2 cell-independent mechanisms of TSLP in cancer rely on TSLP-induced signalling in TSLP receptor (TSLPR)-expressing tumour cells or B cell precursors. TSLP signalling in cancer cells can inhibit apoptosis, leading to tumour progression. Regulatory B cells induced by TSLPR signalling impair antitumour immunity in the tumour microenvironment, enabling metastasis. TSLP signalling in T cells prevents accumulation of CD11b⁺GR1⁺ myeloid cells that produce WNT ligands activating the WNT–β-catenin pathway in the epithelium, which can lead to carcinogenesis and tumour growth. CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte-macrophage colony-stimulating factor; MDSC, myeloid-derived suppressor cell; PDGF, platelet-derived growth factor; T_reg cell, regulatory T cell.