Epithelial cell-derived cytokines: more than just signaling the alarm

Abstract

The epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as "alarmins" that are released by the barrier epithelium in response to external insults, these epithelial cell-derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. However, TSLP, IL-33, and IL-25 all regulate a broad spectrum of innate immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2s) that may act throughout allergic inflammation. Recent data suggest that a TSLP/ILC axis may mediate steroid resistance in asthma. Recent identification of memory Th2 cell subsets that are characterized by high receptor expression for TSLP, IL-33, and IL-25 further supports a role for these cytokines in allergic exacerbations. There is therefore growing interest in developing biologics that target TSLP, IL-33, and IL-25. This Review provides an overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell-derived cytokines.

Figure 1. TSLP, IL-33, and IL-25 regulate a diversity of responses in type 2 immunity.

(A) IL-33 release in the lungs at birth helps establish the pulmonary immune environment, which can influence asthma risk and development later in life. (B) TSLP acts directly on DCs to drive Th2 cell development; IL-25, along with IL-4, can also drive Th2 cell differentiation. (C) TSLP, IL-33, and IL-25 act on a broad array of innate immune cells and are particularly important in eliciting and activating ILC2s; IL-25 can also elicit MPP type 2 cells and IL-17⁺ KLRG1^hi cells. (D) TSLP and IL-33 can act on sensory neurons to stimulate the itch response. (E) TSLP, IL-33, and IL-25 can promote adaptive type 2 responses through subsets of memory Th2 cells that are characterized by high receptor expression for TSLP, IL-33, and IL-25.