Tumor-derived immuno-modulators induce overlapping pro-tolerogenic gene expression signatures in human dendritic cells.
Immature dendritic cells (iDCs) and tolerogenic DCs are essential for the induction and maintenance of peripheral tolerance. Tumors produce immuno-modulatory factors which imprint a pro-tolerogenic, maturation-resistant state in DCs. Here we asked for common markers of differentially tolerized human monocyte-derived DC populations. For this, PBMC-derived monocytes were differentiated to DCs in the presence of established immuno-modulators as released by tumors (IL-6, IL-10, TGF-β, glucocorticoid [GC], prostaglandin E2[PGE2]). Most unstimulated pro-tolerogenic DC populations commonly over-expressed some tolerance-associated markers (ILT-4, IL-10, HO-1) as compared with iDCs. These markers may contribute to imprint a pro-tolerogenic state in DCs. Furthermore, some tolerance markers were overexpressed in an immuno-modulator specific manner in DCs differentiated in the presence of TGF-β (overexpressed tolerance markers: B7-H3, CD103, TGF-β1), IL-10 (B7-DC, ILT-3) and PGE2(IDO). Upon stimulation, matured control DCs (mDCs) down-regulated most pro-tolerogenic markers monitored, while some were upregulated (IkBα, IDO, B7-H1, B7-DC). In contrast, the different groups of tolerized DCs largely retained expression of pro-tolerogenic markers after stimulation. In contrast to mDCs, most groups of tolerized DCs showed impaired upregulation of CD80, and all groups retained IL-10 cytokine production after stimulation. All tolerized DC populations commonly exerted an attenuated allogenic T cell stimulatory capacity as compared with mDCs.
Department of Dermatology, Johannes Gutenberg-University, Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany.
Stefanie
S
Trojandt
Department of Dermatology, Johannes Gutenberg-University, Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany.
Iris
I
Bellinghausen
Department of Dermatology, Johannes Gutenberg-University, Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany.
Angelika B
AB
Reske-Kunz
Department of Dermatology, Johannes Gutenberg-University, Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany. Electronic address: mbros@uni-mainz.de.
Matthias
M
Bros
D017951:Antigen Presentation; D018122:B7-1 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors / Q000378:metabolism*; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D018122:B7-1 Antigen; D016207:Cytokines; D005938:Glucocorticoids; D007155:Immunologic Factors; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D015232:Dinoprostone
Dendritic cells; Dexamethason; Interleukin-10; Prostaglandin E2; Tolerogenic