CD326loCD103loCD11blo Dermal Dendritic Cells Are Activated by Thymic Stromal Lymphopoietin during Contact Sensitization in Mice

Abstract

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 CD326loCD103loCD11blo 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.

Transcriptional Control of Dendritic Cell Development

“…Conditional Klf4 deletion using CD11c-cre impaired Th2 cell responses during S. mansoni infection, Schistosoma egg antigen (SEA) immunization, and HDM challenge and promoted Irf4 expression in pre-cDCs (20). Involvement of a similar subset of CD11b lo DCs in Th2 response had been suggested previously (66). …”

Klf4 Expression in Conventional Dendritic Cells Is Required for T Helper 2 Cell Responses

“…The DN migratory cDCs identified here as being Klf4 -dependent have been described recently to acquire fluorescently labeled antigen from non-viable Nippostrongylus larvae and suggested to be involved in Th2 cell responses based on in vitro analysis (Ochiai et al, 2014; Connor et al, 2014). Our results would support those conclusions by drawing a correlation between the loss of the DN cDC subset and reduced in vivo Th2 cell responses in Klf4 deficient mice.…”

Functions of Murine Dendritic Cells

“…Notch2 f/f Itgax-cre mice did exhibit gene expression changes in remaining cDC1s and cDC2s, however, indicating possible effects of Notch2 in these lineages (Satpathy et al, 2013). Conditional deletion of the transcription factor Klf4 with Itgax-cre also led to the depletion of subsets of cDC2s (Tussiwand et al, 2015) similar to migratory CD24− CD11b− cDC2s in skin-draining LNs (Ochiai et al, 2014). …”