Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Jurkin, Jennifer²  Krump, Corinna¹  Koeffel, Rene²  Fieber, Christina²  Schuster, Christopher³  Brunner, Patrick M.³  Borek, Izabela¹  Eisenwort, Gregor²  Lim, Clarice^1,2  Mages, Joerg⁶  Lang, Roland⁶  Bauer, Wolfgang³  Mechtcheriakova, Diana^4,5  Meshcheryakova, Anastasia^4,5  Elbe-Burger, Adelheid³  Stingl, Georg³  Strobl, Herbert^1,2 

[1] Med Univ Graz, Inst Pathophysiol & Immunol, Heinrichstr 31A, A-8010 Graz, Austria

[2] Med Univ Vienna, Inst Immunol, Vienna, Austria

[3] Med Univ Vienna, Div Immunol Allergy & Infect Dis, Dept Dermatol, Vienna, Austria

[4] Med Univ Vienna, Dept Pathophysiol, Vienna, Austria

[5] Med Univ Vienna, Dept Allergy Res, Vienna, Austria

[6] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Clin Microbiol Immunol & Hyg, Erlangen, Germany

关键词: Kruppel-like factor 4;    Runt-related transcription factor 3;    TGF-beta 1 signaling;    Notch;    lineage decision;    monocyte differentiation;   

DOI  :  10.1016/j.jaci.2016.09.018

来源: Elsevier

【 摘 要 】

Background: Langerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal DCs (dDCs)/interstitial-type DCs and inflammatory dendritic epidermal cells appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency. Objective: Dendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood. Methods: In vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification. Results: Here we identified the monocyte/macrophage lineage identity transcription factor Kruppel-like factor 4 (KLF4) to be inhibited during LC differentiation from human blood monocytes. Conversely, KLF4 is maintained or induced during dermal DC and monocyte-derived dendritic cell/inflammatory dendritic epidermal cell differentiation. We showed that in monocytic cells KLF4 has to be repressed to allow their differentiation into LCs. Moreover, respective KLF4 levels in DC subsets positively correlate with proinflammatory characteristics. We identified epithelial Notch signaling to repress KLF4 in monocytes undergoing LC commitment. Loss of KLF4 in monocytes transcriptionally derepresses Runt-related transcription factor 3 in response to TGF-beta 1, thereby allowing LC differentiation marked by a low cytokine expression profile. Conclusion: Monocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.

【 授权许可】

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