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Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor¹

Claudia Monari^*, Thomas R. Kozel, Francesca Paganelli^*, Eva Pericolini^*, Stefano Perito^*, Francesco Bistoni^*, Arturo Casadevall and Anna Vecchiarelli^2,*

^* Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy; Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557; and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461

A microbial polysaccharide (glucuronoxylomannan (GXM)) exerts potent immunosuppression by direct engagement to immunoinhibitory receptor FcRIIB. Activation of FcRIIB by GXM leads to the recruitment and phosphorylation of SHIP that prevents IB activation. The FcRIIB blockade inhibits GXM-induced IL-10 production and induces TNF- secretion. GXM quenches LPS-induced TNF- release via FcRIIB. The addition of mAb to GXM reverses GXM-induced immunosuppression by shifting recognition from FcRIIB to FcRIIA. These findings indicate a novel mechanism by which microbial products can impair immune function through direct stimulation of an inhibitory receptor. Furthermore, our observations provide a new mechanism for the ability of specific Ab to reverse the immune inhibitory effects of certain microbial products.

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 the National Institute of Health AIDS Project No. 50 F.36, Basic Research Investment Funds Project No. RBLA03C9F4_006, Public Health Service Grant AI14209, and from the National Institute for Allergy and Infectious Diseases (to T.R.K.). A.C. is supported in part by Public Health Service Grant HL059842.

² Address correspondence and reprint requests to Professor Anna Vecchiarelli, Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. E-mail address: vecchiar{at}unipg.it

³ Abbreviations used in this paper: GXM, glucuronoxylomannan; MFI, mean fluorescence intensity; P-, phospho-; FLUOS, 5(6)-carboxyfluorescein-N-hydroxysuccinimide ester.