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

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. Dendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood. In vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification. 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-β1, thereby allowing LC differentiation marked by a low cytokine expression profile. Monocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.

Jurkin J ，Krump C ，Köffel R ，Fieber C ，Schuster C ，Brunner PM ，Borek I ，Eisenwort G ，Lim C ，Mages J ，Lang R ，Bauer W ，Mechtcheriakova D ，Meshcheryakova A ，Elbe-Bürger A ，Stingl G ，Strobl H ... -  《-》

Uncovering the Mysteries of Langerhans Cells, Inflammatory Dendritic Epidermal Cells, and Monocyte-Derived Langerhans Cell-Like Cells in the Epidermis.

Otsuka M ，Egawa G ，Kabashima K 《Frontiers in Immunology》

Reciprocal role of GATA-1 and vitamin D receptor in human myeloid dendritic cell differentiation.

Göbel F ，Taschner S ，Jurkin J ，Konradi S ，Vaculik C ，Richter S ，Kneidinger D ，Mühlbacher C ，Bieglmayer C ，Elbe-Bürger A ，Strobl H ... -  《-》

Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo.

Alder JK ，Georgantas RW 3rd ，Hildreth RL ，Kaplan IM ，Morisot S ，Yu X ，McDevitt M ，Civin CI ... -  《-》

Microenvironmental and cell intrinsic factors governing human cDC2 differentiation and monocyte reprogramming.

cDC2s occur abundantly in peripheral tissues and arise from circulating blood cDC2s. However, the factors governing cDC2 differentiation in tissues, especially under inflammatory conditions, remained poorly defined. We here found that psoriatic cDC2s express the efferocytosis receptor Axl and exhibit a bone morphogenetic protein (BMP) and p38MAPK signaling signature. BMP7, strongly expressed within the lesional psoriatic epidermis, cooperates with canonical TGF-β1 signaling for inducing Axl+cDC2s from blood cDC2s in vitro. Moreover, downstream induced p38MAPK promotes Axl+cDC2s at the expense of Axl+CD207+ Langerhans cell differentiation from blood cDC2s. BMP7 supplementation allowed to model cDC2 generation and their further differentiation into LCs from CD34+ hematopoietic progenitor cells in defined serum-free medium. Additionally, p38MAPK promoted the generation of another cDC2 subset lacking Axl but expressing the non-classical NFkB transcription factor RelB in vitro. Such RelB+cDC2s occurred predominantly at dermal sites in the inflamed skin. Finally, we found that cDC2s can be induced to acquire high levels of the monocyte lineage identity factor kruppel-like-factor-4 (KLF4) along with monocyte-derived DC and macrophage phenotypic characteristics in vitro. In conclusion, inflammatory and psoriatic epidermal signals instruct blood cDC2s to acquire phenotypic characteristics of several tissue-resident cell subsets.

Lang M ，Krump C ，Meshcheryakova A ，Tam-Amersdorfer C ，Schwarzenberger E ，Passegger C ，Connolly S ，Mechtcheriakova D ，Strobl H ... -  《Frontiers in Immunology》