Thymic stromal lymphopoietin

Abstract

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine expressed in skin, gut, lungs, and thymus. TSLP signals via a TSLP receptor (TSLPR), a heterodimer of the IL-7 receptor alpha chain and the TSLPR chain. The TSLPR chain is closely related to the common receptor gamma chain that is expressed on a wide range of cell types in the adaptive and innate immune system. TSLP exerts a profound influence on the polarization of dendritic cells to drive T helper (Th) 2 cytokine production. TSLP also directly promotes T-cell proliferation in response to T-cell receptor activation and Th2 cytokine production and supports B-cell expansion and differentiation. TSLP further amplifies Th2 cytokine production by mast cells and natural killer T cells. These properties confer on TSLP a critical role in driving Th2-mediated inflammation. This role is supported by the finding that TSLP expression is upregulated in keratinocytes of atopic dermatitis skin lesions and in bronchial epithelial cells in asthma.

Figure 1

Structure of the heterodimeric TSLP receptor and the its cellular targets immune cells. TSLPR signals via activation and phosphorylation of STAT5 (P-STAT5) and other unidentified pathways. Adapted from Nature Immunol. 2009; 7: 709-714

Figure 2

TSLP expression in epidermis of skin from patients with atopic dermatitis but not from healthy control. (A) No detectable TSLP expression (no red staining). in epidermis from skin of health control. (B) High expression of TSLP (red staining) in epidermis from skin lesion of atopic dermatitis. Adapted from Adv Immunol. 2009; 101:1-25

Figure 3

TSLP acts through multiple pathways in Th2 cell differentiation and Th2 cytokine production. Adapted from Journal of Allergy and Clinical Immunology, 2007;120 (2): 238-244.

Figure 4

K5-TLSP transgenic mice develop a AD-like dermatitis. (A). Immunohistochemical staining showing TSLP expression (brown) in the epidermis and its basement membrane from skin of a K5-TSLP mouse as compared with normal littermate control (NLC). (B) Skin sections stained with H&E showing pronounced acanthosis (arrow) and dermal infiltration by mast cells (arrows) and eosinophils (arrowheads) at 100×.

Figure 5

Attenuated skin inflammation in OVA-challenged skin of i.p. immunized mice treated with neutralizing antibodies to TSLP compared with those treated with isotype control. (A) Number of infiltrating eosinophils and CD4+ cells. (B) expression of mRNA for IL-4 and IL-13. Proc Natl Acad Sci U S A. 2008; 105(33):11875-80