Thymic Stromal Lymphopoietin (TSLP) is an interleukin-7-like messenger protein, or cytokine, that plays a significant role in immune system communication. It is predominantly secreted by epithelial cells lining the body’s barrier surfaces, such as the skin, lungs, and gastrointestinal tract. TSLP acts as an immediate signal between the external environment and the immune system, instructing immune cells on how to respond to stimuli. Understanding TSLP’s function is central to deciphering the origins and progression of allergic and chronic inflammatory conditions.
TSLP’s Function in Healthy Tissue
In a healthy state, TSLP maintains a low, baseline level of expression, contributing to the routine surveillance and balance of the immune system. This low-level presence helps the body distinguish between harmless environmental factors and actual threats, a process known as immune tolerance. TSLP is involved in the positive selection of regulatory T (Treg) cells within the thymus.
In peripheral tissues like the gut, TSLP signaling helps maintain coexistence with the commensal microbiome. It engages local dendritic cells (DCs), instructing them to promote tolerance rather than an inflammatory reaction. This homeostatic function is important for preventing the unnecessary activation of the immune system against benign substances or the body’s own internal environment.
The Role of TSLP as an Immune Alarm Signal
TSLP transitions from a homeostatic regulator to a powerful immune “alarmin” when barrier surfaces are damaged or stressed. Epithelial cells rapidly release large, sustained quantities of TSLP in response to external threats like allergens, viral particles, bacterial products, or physical injury. This massive surge acts as a first-responder signal, initiating an immediate and powerful immune response.
Once released, TSLP binds to a heterodimeric receptor complex on the surface of various immune cells, most notably dendritic cells. This binding potently activates the dendritic cells, causing them to mature and upregulate their expression of molecules like MHC class II and co-stimulatory proteins. The activated dendritic cells then migrate to nearby lymph nodes, where they present antigens to naïve T cells, programming them for an allergic response.
TSLP is a primary driver of the Type 2 inflammatory cascade, which is characteristic of allergic disease. TSLP-activated dendritic cells instruct T cells to differentiate into Type 2 helper (Th2) cells. These Th2 cells subsequently produce pro-allergic cytokines, including Interleukin-4 (IL-4), IL-5, and IL-13, which amplify the inflammatory signal. TSLP also directly acts on innate lymphoid cells (ILC2s), which are a potent source of these Type 2 cytokines, ensuring the rapid initiation of the allergic response.
Link Between TSLP and Chronic Allergic Disease
Sustained, high-level TSLP signaling is directly implicated in the development and perpetuation of chronic allergic conditions. The Th2 cytokines produced downstream of TSLP recruit and activate inflammatory cells, such as eosinophils and mast cells. They also promote B cells to switch to producing Immunoglobulin E (IgE), the key antibody in allergic reactions. This creates a self-sustaining inflammatory loop that defines conditions like asthma and atopic dermatitis.
Atopic Dermatitis
In Atopic Dermatitis (eczema), high TSLP expression is found in affected skin lesions, often triggered by a defective skin barrier. TSLP signaling drives a local Type 2 response that leads to intense itching, inflammation, and further barrier dysfunction characteristic of the disease. This skin-derived TSLP is also thought to be a driver of the “atopic march,” the sequential progression from eczema to other allergic diseases like asthma.
Asthma
TSLP is a major factor in the pathogenesis of asthma, particularly in severe, uncontrolled forms. In the airways, TSLP expression correlates with disease severity and promotes chronic inflammation that leads to structural changes in the lungs. The persistent release of Type 2 mediators fosters airway hyperresponsiveness and encourages tissue remodeling, such as the thickening of the airway walls and the overproduction of mucus. Genetic variations in the TSLP gene that increase its expression have been identified as susceptibility factors for developing asthma and Eosinophilic Esophagitis.
Therapeutic Strategies to Inhibit TSLP
Because TSLP sits at the beginning of the allergic inflammatory cascade, blocking its action is a highly effective therapeutic strategy. This “upstream” approach aims to neutralize the initial alarm signal before it can fully activate the entire cascade of Type 2 immune cells and mediators. By preventing the initial programming of the immune response, TSLP inhibition addresses the underlying cause of the inflammation rather than just managing its downstream effects.
The most successful current strategy involves the use of monoclonal antibodies designed to specifically target TSLP. Tezepelumab, for example, is a fully human monoclonal antibody that binds directly to the TSLP protein. This binding neutralizes TSLP, preventing it from connecting with its receptor complex on immune cells.
By blocking TSLP from initiating the response, Tezepelumab significantly reduces the production of all downstream Type 2 cytokines, including IL-4, IL-5, and IL-13. This intervention has demonstrated efficacy in treating severe, uncontrolled asthma, showing benefits regardless of the patient’s baseline levels of Type 2 biomarkers. Other therapeutic approaches under investigation include antibodies that block the TSLP receptor complex itself, offering an alternative way to disrupt the signaling pathway.