Egr2 induced during DC development acts as an intrinsic negative regulator of DC immunogenicity

Abstract

Early growth response gene 2 (Egr2), which encodes a zinc finger transcription factor, is rapidly and transiently induced in various cell types independently of de novo protein synthesis. Although a role for Egr2 is well established in T-cell development, Egr2 expression and its biological function in dendritic cells (DCs)have not yet been described. Here, we demonstrate Egr2 expression during DC development, and its role in DC-mediated immune responses. Egr2 is expressed in the later stage of DC development from BM precursor cells. Even at steady state, Egr2 is highly expressed in mouse splenic DCs. Egr2-knockdown (Egr2-KD) DCs showed increased levels of major histocompatability complex (MHC) class I and II and co-stimulatory molecules, and enhanced antigen uptake and migratory capacities. Furthermore, Egr2-KD abolished SOCS1 expression and signal transducer and activator of transcription 5 (STAT5) activation during DC development, probably resulting in the enhancement of IL-12 expression and Th1 immunogenicity of a DC vaccine. DC-mediated cytotoxic T lymphocyte (CTL) activation and antitumor immunity were significantly enhanced by Egr2-KD, and impaired by Egr2 overexpression in antigen-pulsed DC vaccines. These data suggest that Egr2 acts as an intrinsic negative regulator of DC immunogenicity and can be an attractive molecular target for DC vaccine development.Keywords: DC development r Egr2 r Immunotherapy r Negative regulator r Th1 immunity Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) consist of several phenotypic and functionally distinct subsets. Given their multiple functions in host immunity, Correspondence: Prof. Yong-Soo Bae e-mail: ysbae04@skku.edu there has been great interest in elucidating the mechanisms controlling the development of DCs from bone marrow (BM) precursor cells. However, the detailed molecular mechanisms underlying DC differentiation from BM or HSCs remain widely unknown [1].In our previous report, we showed that a cytokine inducible SH2-domain protein, as a positive regulator, facilitates DC differentiation to become a potent stimulator of cytotoxic T lymphocytes (CTLs) [2]. Here, we focused on the function of early C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2484-2496 Molecular immunology 2485 growth response gene 2 (Egr2), a zinc finger transcription factor, in DC development and DC-mediated immunogenicity.In the present study, we found that Egr2 is strongly induced during the later stage of DC development and acts as an intrinsic negative regulator of DC development and DC-mediated immunogenicity. Egr2 is well established in the growth, differentiation, and function of several cell types. Egr2 was reported to inhibit suppressor of cytokine signaling 1 (SOCS-1) expression and upregulate Bcl-2 during positive selection of thymocytes [3]. Loss of Egr2 causes downregulation of IL-7R, upregulation of SOCS-1 mRNA, inhibition of signa...

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