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Increased Expression of Leukocyte Ig-Like Receptor-1 and Activating Role of UL18 in the Response to Cytomegalovirus Infection¹

Claudia S. Wagner^2,*, Gerdt C. Riise, Tomas Bergström, Klas Kärre, Ennio Carbone^,¶ and Louise Berg

^* Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergology and Department of Clinical Virology, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden; Department of Microbiology, Tumor and Cell Biology and Strategic Research Center for Studies of Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden; and ^¶ Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia," Catanzaro, Italy

NK and T cells are important for combating CMV infection. Some NK and T cells express leukocyte Ig-like receptor-1 (LIR-1), an inhibitory receptor recognizing MHC class I and the CMV-encoded homolog UL18. We previously demonstrated an early increase in LIR-1-expressing blood lymphocytes in lung-transplanted patients later developing CMV disease. We now show that NK and T cells account for the observed LIR-1 augmentation. Coincubation of PBMC from CMV-seropositive donors with virus-infected lung fibroblasts led to a T cell-dependent secretion of IFN-, produced mainly by LIR-1⁺ T cells and by NK cells. Cytokine production during coculture with fibroblasts infected with virus containing the UL18 gene was augmented compared with the UL18 deletion virus, suggesting a stimulatory role for UL18. However, purified UL18Fc proteins inhibited IFN- production of LIR-1⁺ T cells. We propose that cytokine production in the transplant induces NK and T cells to express LIR-1, which may predispose to CMV disease by MHC/LIR-1-mediated suppression. Although the UL18/LIR-1 interaction could inhibit T cell responses, this unlikely plays a role in response to infected cells. Instead, our data point to an activating role for viral UL18 during infection, where indirect intracellular effects cannot be excluded.

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 grants from the Swedish Heart-Lung Foundation, Swedish Cancer Society, King Gustaf V 80th Jubilee Fund, Västra Götaland’s Region, and the Swedish Society of Medicine. E.C. was supported by European Union Grant ERBFM-BICT 972110 and by Associazione Italiana per la Ricerca Cancro.

² Address correspondence and reprint requests to Dr. Claudia S. Wagner, Center for Infectious Medicine, F59, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. E-mail address: claudia.wagner{at}ki.se

³ Abbreviations used in this paper: HCMV, human CMV; MCMV, mouse CMV; BAL, bronchoalveolar lavage; HL, human embryonic lung; LIR, leucocyte Ig-like receptor; MOI, multiplicity of infection; p.i., postinfection; MFI, mean fluorescence intensity; MIC, MHC class I polypeptide-related sequence; PVR, poliovirus receptor; ULBP, UL16 binding protein; CMVd⁺/CMVd^–, CMV disease positive/negative.

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