Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP

Abstract

Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (TH2)-type allergic inflammation is not known. We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c+ dendritic cells (DCs) and induced production of the TH2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22). TSLP-activated DCs primed naïve TH cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-α, while down-regulating IL-10 and interferon-γ. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis. TSLP expression was associated with Langerhans cell migration and activation in situ. These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation.

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Figure 1: TSLP potently activates CD11c+ DCs and maintains their survival.
Figure 2: Naïve CD4+ T cell proliferation and expansion with DCs activated by TSLP and other activators.
Figure 3: Cytokine and chemokine production by DCs activated with TSLP.
Figure 4: Cytokine production by naïve CD4+ T cells primed for 6 days with TSLP-DCs.
Figure 5: Quantification of TSLP mRNA levels in different human hematopoietic and stromal cell types.
Figure 6: Expression of TSLP by crypt epithelial cells of human inflamed tonsils.
Figure 7: Sporadic expression of TSLP by squamous epithelial cells of inflamed tonsils is associated with the presence of activated DC-LAMP+ DCs.
Figure 8: Expression of TSLP in atopic dermatitis.
Figure 9: TSLP expression in atopic dermatitis associates with Langerhans cell migration and activation.

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Acknowledgements

We thank L. Lanier, J.-Z. Chen and J. Banchereau for critical reading of the manuscript and M. Andonian for help with graphics. DNAX Research Institute is supported by Schering-Plough.

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Correspondence to Yong-Jun Liu.

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DNAX Research Inc is a wholly owned subsidiary of the Schering Corporation, Kenilworth, NJ.

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