Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that has emerged as a critical player in the development and progression of allergy and asthma. It is primarily produced by epithelial cells and functions as a potent immune system activator. TSLP acts through interaction with its receptor complex, composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha chain (IL-7Rα), activating downstream complex signalling pathways. The TSLP major isoform, known as long-form TSLP (lfTSLP), is upregulated in the airway epithelium of patients with allergic diseases. More research is warranted to explore the precise mechanisms by which short-form TSLP (sfTSLP) regulates immune responses. Understanding the dynamic interplay between TSLP and the dysfunctional epithelium provides insights into the mechanisms underlying allergy and asthma pathogenesis. Targeting TSLP represents an important therapeutic strategy, as it may upstream disrupt the inflammatory cascade and alleviate symptoms associated with allergic inflammation.

Keywords: allergy; asthma; epithelium; thymic stromal lymphopoietin.

Figure 1

Graphic representation of the pro-inflammatory TSLP mediated complex and its intracellular signalling pathways (adapted after [1,13,14,15,16]). TSLP with an atypical open helical bundle core, wedges between TSLPR and IL-7Rα to mediate the T-shaped extracellular assembly. The brown star indicates site I (TSLP:TSLPR interface) with pronounced electrostatic complementarity, the blue star denotes site II (TSLP:IL-7Rα interface) and the orange one site III (IL-7Rα:TSLPR interface). TSLP, represented here in green, is the long-form TSLP (the common part with the short-form TSLP is presented in light green). The hidden red star highlights the binding region of tezepelumab overlapped by the binding region on TSLP on TSLPR. The parts noted 1, 2, and 3 of this figure represent complex molecular events at the receptor (1), transcription factors (2) and target genes (3) levels, as explained in the text.

Figure 2

Schematic simplified representation of the molecular binding of the monoclonal antibody tezepelumab to the human TSLP with subsequent blocking of its interaction with the heterodimeric TSLP receptor, thus impeding the formation of the TSLPR: TSLP: IL-7Rα ternary complex on effector cells. The CDRs of the VH of tezepelumab target TSLP at the C-terminal region of helix αD and AB loop region (marked by red star), while the VL does not interact with TSLP (adapted after [15]). TSLP represented here in green is the long-form TSLP (the common part with the short-form TSLP is highlighted in light green).

Figure 3

Long form TSLP (lfTSLP), consisting of 159 amino acids (AA), has four α-helices (αA, αB, αC, αD) linked by a BC loop and two longer AB and CD loop regions. Short form TSLP is 63 AA residues in length and covers the C-terminal half of human TSLP (residues 97–159) (adapted after [15]). The regions employed by TSLP to interact with the cytokine-binding homology region of TSLPR are marked in boxes in blue. Tezepelumab targets TSLP at the C-terminal region of helix D and AB loop region. The plasticity of the π-helical turn in αA has an critical functional role in the priming of TSLP by TSLPR to enable high-affinity binding by IL-7Rα; therefore, IL-7Rα cannot be recruited to the TSLP:tezepelumab complex.

Figure 4

TSLP: environmental inducers, cellular sources and its variety of targets and actions (adapted after [1,46,47]).