CD326CD103CD11b Dermal Dendritic Cells Are Activated by Thymic Stromal Lymphopoietin during Contact Sensitization in Mice

The cytokine thymic stromal lymphopoietin (TSLP) is produced by epithelia exposed to the contact sensitizer dibutyl phthalate (DBP), and it is critical for the induction of Th2 immune responses by DBP-FITC. TSLP is thought to act on dendritic cells (DC), but the precise DC subsets involved in the response to TSLP remain to be fully characterized. In this study we show that a subset of CD326 lo CD103 lo CD11b lo dermal DC, which we termed " triple-negative (TN) DC, " is highly responsive to TSLP. In DBP-FITC– treated mice, TN DC upregulated expression of CD86 and rapidly migrated to the draining lymph node to become the most abundant skin-derived DC subset at 24 and 48 h after sensitization. None of these responses was observed in TSLPR-deficient mice. In contrast, TN DC numbers were not increased after treatment with the allergen house dust mite or the bacteria Escherichia coli and bacillus Calmette–Guérin, which increased other DC subsets. In vivo, treatment with rTSLP preferentially increased the numbers of TN DC in lymph nodes. In vitro, TN DC responded to rTSLP treatment with a higher level of STAT5 phosphorylation compared with other skin-derived DC subsets. The TN DC subset shared the morphology, phenotype, and developmental requirements of conventional DC, depending on FLT3 expression for their optimal development from bone marrow precursors, and CCR7 for migration to the draining lymph node. Thus, TN DC represent a dermal DC subset that should be considered in future studies of TSLP-dependent contact sensitization and skin immune responses. T hymic stromal lymphopoietin (TSLP) is an epithelial innate cytokine primarily expressed in the intestinal tract, as well as in the skin and lung during inflammation and TLR ligation (1). TSLP binds to a receptor complex composed of an IL-7Ra chain and a TSLP-specific TSLPR chain (2, 3). TSLP has been associated with a wide range of immune responses, including allergic responses (4–6), but also CD8 + T cell responses such as those induced by influenza viruses (7). TSLP is highly expressed in contact dermatitis and has been shown to play a key role in the Th2 response to dibutyl phthalate (DBP) (8), a plasticizer with adjuvant properties used during the sensitization stage of FITC-induced contact hypersensitivity (9). Compared to TSLPR-sufficient mice, TSLPR-deficient mice exposed to DBP-FITC generate significantly reduced Th2-type responses as measured by skin thickening, Th2 cytokine production in skin–draining lymph node (dLN), and serum IgE levels …