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Involvement of Glycoreceptors in Galactoxylomannan-Induced T Cell Death¹

Eva Pericolini^2,*, Elena Gabrielli^2,*, Elio Cenci^*, Magdia De Jesus, Francesco Bistoni^*, Arturo Casadevall and Anna Vecchiarelli^3,*

^* Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy; and Department of Microbiology and Immunology of the Albert Einstein College of Medicine, Bronx, New York 10461

The major virulence factor of Cryptococcus neoformans is its capsular polysaccharide, which is also released into tissues. The shed polysaccharide is composed of glucuronoxylomannan, galactoxylomannan (GalXM), and mannoproteins. In a previous study, we demonstrated a direct interaction of purified soluble GalXM with T cells that induced their apoptosis. In this study, we focus on the mechanisms involved in the apoptotic effect of GalXM. In our experimental system, we analyzed the effect of GalXM on purified human T cells and Jurkat cells, a T cell line routinely used for apoptotic studies. Our results reveal that GalXM activates the extrinsic and intrinsic apoptotic pathways through the cleavage and recruitment of caspase-8. Caspase-8 elicits the downstream executioner caspase-3, caspase-6, and caspase-7 both directly and indirectly, via Bid cleavage and caspase-9 activation. These effects appeared to be primarily mediated by the interaction of GalXM with the glycoreceptors, which differed in human T and Jurkat cells. CD45 was primarily involved in Jurkat cells apoptosis while CD7 and CD43 mediated human T cell apoptosis. Our results highlight a new mechanism by which a microbial product can contribute to virulence through direct interaction with T cell glycoreceptors, thereby triggering lymphocyte apoptosis.

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 Public Health Service Grant AI14209 from the National Institutes of Health and Investment for Basic Research, protocol No. RBLA03C9F4_006. A.C. and M.D.J. were supported by National Institutes of Health Grants R01AI033774-15, R01HL059842-12, and R37AI033142.

² E.P. and E.G. contributed equally to the paper.

³ Address correspondence and reprint requests to Prof. Anna Vecchiarelli, Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, Perugia, Italy. E-mail address: vecchiar{at}unipg.it

⁴ Abbreviations used in this paper: GXM, glucuronoxylomannan; GalXM, galactoxylomannan; FasL, Fas ligand; PI, propidium iodide; RT, room temperature; FB, fluorescence buffer; tBid, truncated Bid.

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