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17β-Estradiol Alters the Activity of Conventional and IFN-Producing Killer Dendritic Cells¹

Mark C. Siracusa^*, Michael G. Overstreet^*, Franck Housseau, Alan L. Scott^* and Sabra L. Klein^2,*

^* The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231

Estrogens increase aspects of innate immunity and contribute to sex differences in the prevalence of autoimmune diseases and in response to infection. The goal of the present study was to assess whether exposure to 17β-estradiol (E2) affects the development and function of bone marrow-derived dendritic cells and to determine whether similar changes are observed in CD11c⁺ splenocytes exposed to E2 in vivo. E2 facilitated the differentiation of BM precursor cells into functional CD11c⁺CD11b⁺MHC class II⁺ dendritic cells (DCs) with increased expression of the costimulatory molecules CD40 and CD86. Exposure of bone marrow-derived dendritic cells to E2 also enhanced production of IL-12 in response to the TLR ligands, CpG and LPS. In contrast, CD11c⁺ cells isolated from the spleens of female C57BL/6 mice that were intact, ovariectomized, or ovariectomized with E2 replacement exhibited no differences in the number or activity of CD11c⁺CD11b⁺MHC class II⁺ DCs. The presence of E2 in vivo, however, increased the number of CD11c⁺CD49b⁺NK1.1^low cells and reduced numbers of CD11c⁺CD49b⁺NK1.1^high cells, a surface phenotype for IFN-producing killer DCs (IKDCs). Ultrastructural analysis demonstrated that CD11c⁺NK1.1⁺ populations were comprised of cells that had the appearance of both DCs and IKDCs. CD11c⁺ splenocytes isolated from animals with supplemental E2 produced more IFN- in response to IL-12 and IL-18. These data illustrate that E2 has differential effects on the development and function of DCs and IKDCs and provide evidence that E2 may strengthen innate immunity by enhancing IFN- production by CD11c⁺ cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 AI 054995 (to S.L.K.) and a grant from The Johns Hopkins Malaria Research Institute (to S.L.K.).

² Address correspondence and reprint requests to Dr. Sabra Klein, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205. E-mail address: saklein{at}jhsph.edu

³ Abbreviations used in this paper: E2, 17β-estradiol; ER, estrogen receptor; ERE, estrogen response element; DC, dendritic cell; BM, bone marrow; cDC, conventional dendritic cell; pDC, plasmacytoid dendritic cell; IKDC, interferon-producing killer dendritic cell; ovx, ovariectomized; sham, sham surgery; WT, wild type; MHCII, MHC class II; IMDM, Iscove’s modified Dulbecco’s medium.