Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity

Abstract

Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-γ-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell α-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p ≤ 0.018). TSLP and TARC/CCL17 expression correlated with airway obstruction. Although the total numbers of cells expressing CCR4, CCR8, and CXCR3 did not significantly differ in the asthmatics and controls, there was evidence of selective infiltration of CD4+/CCR4+ T cells in the asthmatic biopsies which correlated with TARC and MDC expression and airway obstruction. Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines. Our data implicate TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10 in asthma pathogenesis. These may act partly through selective development and retention, or recruitment of Th2 cells bearing their receptors.

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

“…We now show that activated human CD4 ϩ T cells express TSLPR and that TSLP can rapidly activate Stat5 and induce expression of Stat5 target genes. The greater effect of TSLP on activated than on resting T cells correlates with its induction by inflammatory processes (14,15) and the activation-induced expression of TSLPR that we now show. The ability of TSLP to induce IL-2R␣ expression may explain the higher sensitivity of CD4 ϩ T cells to low doses of IL-2 in the presence of TSLP, and it is possible that such an increase might augment an immune response even in a setting of low TCR engagement.…”

“…TSLP has been implicated in the development of asthma and atopic dermatitis (11)(12)(13)(14)(15). TSLPR KO mice have a defective lung inflammatory allergic response, but this is reversed by adoptive transfer of WT CD4 ϩ T cells (11).…”

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

“…Based upon the observation that airway epithelium cells directly affected T cell activation, we decided to test candidate factors that had been shown previously to play an inhibitory role in airway or intestinal epithelial cells, including TGF-b, IL-10, TSLP and NO [ [21][22][23]. When analyzing BEAS-2B cells for transcription of known inhibitory mediators, we found that TGF-b transcripts were detectable at high levels (Fig.…”

Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis

“…For instance, transgenic mice expressing TSLP in keratinocytes or in lung epithelial cells have been shown to develop atopic dermatitis-or asthma-like inflammation in the skin or the lung, respectively, while TSLPR null mice failed to develop an inflammatory lung response to inhaled antigen [5][6][7]. In humans, TSLP has been shown to be expressed by keratinocytes in atopic dermatitis and by bronchial epithelial cells in asthmatic airways [8,9].…”

“…For instance, transgenic mice expressing TSLP in keratinocytes or in lung epithelial cells have been shown to develop atopic dermatitis-or asthma-like inflammation in the skin or the lung, respectively, while TSLPR null mice failed to develop an inflammatory lung response to inhaled antigen [5][6][7]. In humans, TSLP has been shown to be expressed by keratinocytes in atopic dermatitis and by bronchial epithelial cells in asthmatic airways [8,9].In contrast to the pro-allergic action of TSLP, regulation of TSLP expression in epithelial cells has not been fully elucidated. Previous studies suggest that TSLP expression in mouse keratinocytes is regulated by vitamin D and retinoic acid signaling [10] [17].…”