Epithelium-innate immune cell axis in mucosal responses to SIV.

• Type of Material: Article
• Authors: L. Shang, University of Minnesota; L. Duan, University of Minnesota; K.E. Perkey, University of Minnesota; S. Wietgrefe, University of Minnesota; M. Zupancic, University of Minnesota; A.J. Smith, University of Minnesota; P.J. Southern, University of Minnesota; Robert Johnson, Emory University; A.T. Haase, University of Minnesota
• Language: English
• Date: 2016-07-20
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016, Rights Managed by Nature Publishing Group.
• Final Published Version (URL): http://dx.doi.org/10.1038/mi.2016.62
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Grant/Funding Information: This work was supported by the International AIDS Vaccine Initiative, National Institutes of Health grants AI071306 and RR00168, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.
• Keywords: Female Genital Tract; pDC; Focal Cluster; CD4 T cells; Macrophage; Early Events; SIV; Cell Recruitment; Epithelium-Innate Immune Cell Axis; Mucosa; Cervix; SIVΔnef; Chemokine; Epithelium
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

In the SIV (simian immunodeficiency virus)-rhesus macaque model of HIV-1 (human immunodeficiency virus type I) transmission to women, one hallmark of the mucosal response to exposure to high doses of SIV is CD4 T-cell recruitment that fuels local virus expansion in early infection. In this study, we systematically analyzed the cellular events and chemoattractant profiles in cervical tissues that precede CD4 T-cell recruitment. We show that vaginal exposure to the SIV inoculum rapidly induces chemokine expression in cervical epithelium including CCL3, CCL20, and CXCL8. The chemokine expression is associated with early recruitment of macrophages and plasmacytoid dendritic cells that are co-clustered underneath the cervical epithelium. Production of chemokines CCL3 and CXCL8 by these cells in turn generates a chemokine gradient that is spatially correlated with the recruitment of CD4 T cells. We further show that the protection of SIVmac239Δnef vaccination against vaginal challenge is correlated with the absence of this epithelium-innate immune cell-CD4 T-cell axis response in the cervical mucosa. Our results reveal a critical role for cervical epithelium in initiating early mucosal responses to vaginal infection, highlight an important role for macrophages in target cell recruitment, and provide further evidence of a paradoxical dampening effect of a protective vaccine on these early mucosal responses.