Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Aleh Bobr, Botond Zoltan Igyarto, Krystal M. Haley, Ming O. Li, Richard A. Flavell, Daniel H Kaplan

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-β1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-β1 is complicated by the requirement of TGF-β1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-β1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreERT2 mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreERT2 x TGF-βRIIfl and huLangerin-CreERT2 x TGF-β1flmice. Excision of the TGFβRII or TGFβ1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration.We conclude that TGF-β1 acts directly on LCs in an autocrine/ paracrine manner to inhibit steady-state and inflammation-induced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.

Original languageEnglish (US)
Pages (from-to)10492-10497
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number26
DOIs
StatePublished - Jun 26 2012

Keywords

  • Skin immunology
  • Tolerance
  • pSMAD2/3

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