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Ly49H⁺ NK Cells Migrate to and Protect Splenic White Pulp Stroma from Murine Cytomegalovirus Infection¹

Vasileios Bekiaris^*, Olga Timoshenko, Tie Zheng Hou^*, Kai Toellner^*, Saba Shakib^*, Fabrina Gaspal^*, Fiona M. McConnell^*, Sonia M. Parnell^*, David Withers^*, Chris D. Buckley^*, Clive Sweet, Wayne M. Yokoyama, Graham Anderson^* and Peter J. L. Lane^2,*

^* Medical Research Council Centre for Immune Regulation, Birmingham Medical School and School of Biosciences, Birmingham, United Kingdom; and Washington University School of Medicine, St. Louis, MO 63110

In this study, we show that in the absence of a protective NK cell response, murine CMV causes destruction of splenic white and red pulp pulp areas in the first few days of infection. Destruction of T zone stroma is associated with almost complete loss of dendritic cells and T cells. We provide evidence that the virus replicates in red and white pulp stroma in vivo and in vitro. Control of white pulp viral replication is associated with migration of murine CMV-specific activated NK cells to white pulp areas, where they associate directly with podoplanin-expressing T zone stromal cells. Our data explain how NK cells protect the lymphoid-rich white pulp areas from CMV, allowing protective adaptive T cell-dependent immune responses to develop, and how this mechanism might break down in immunocompromised patients.

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 a Wellcome Programme grant to P.J.L.L. and G.A.

² Address correspondence and reprint requests to Dr. Peter J. L. Lane, Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, Birmingham Medical School, Birmingham B15 2TT, U.K. E-mail address: p.j.l.lane{at}bham.ac.uk

³ Abbreviations used in this paper: MCMV, murine CMV; DAPI, 4',6'-diamidino-2-phenylindole; DC, dendritic cell; LTβR, lymphotoxin-β receptor; MEF, mouse embryonic fibroblast; MOI, multiplicity of infection.