Sensing the outside world: TSLP regulates barrier immunity

Abstract

Thymic stromal lymphopoietin (TSLP) is an interleukin 7 (IL-7)-like cytokine originally characterized by its ability to promote the activation of B cells and dendritic cells (DCs). Subsequent studies have shown that TSLP promotes T helper type 2 (TH2) cell responses associated with immunity to some helminth parasites and the pathogenesis of many inflammatory diseases, including atopic dermatitis and asthma. This review will focus on recent findings indicating that in addition to influencing B cell and DC function, TSLP can promote TH2 cytokine-associated inflammation by directly promoting the effector functions of CD4+ TH2 cells, basophils and other granulocyte populations while simultaneously limiting the expression of DC-derived proinflammatory cytokines and promoting regulatory T cell responses in peripheral tissues.

Figure 1

Pantheon of TSLP-responsive cells. NKT, natural killer T.

Figure 2

TSLP regulates T_H2 cytokine responses after helminth infection and exposure to allergens. (a) After exposure to helminth parasites, infection and/or disruption of colonic epithelium elicits responses to Toll-like receptor (TLR) and Nod-like receptor agonists that are able to induce IL-12p40 expression and subsequent T_H1 cytokine responses. TSLP, which is also induced during infection, acts to suppress p40 expression by DCs, which inhibits the development of T_H1 responses, while also inducing OX40L to promote T_H2 responses. TSLP may also act to recruit IL-4-producing basophils to draining lymph nodes (LN) that act cooperatively with DCs to prime T_H2 cytokine responses. (b) After allergen exposure, proteases present in the allergen complex activate PAR-2, which in turn induces TSLP expression. TSLP induces resident DCs to upregulate OX40L and to produce chemokines (CCL17 and CCL22) to promote T_H2 responses. TSLP acts on resident mast cells and natural killer T cells to increase cytokine production, which further promotes the T_H2 inflammatory cascade. MHCII, major histocompatibility complex class II.