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Delayed Contraction of the CD8⁺ T Cell Response toward Lymphocytic Choriomeningitis Virus Infection in Mice Lacking Serglycin¹

Mirjana Grujic^*, Jan P. Christensen^*, Maria R. Sørensen^*, Magnus Abrink, Gunnar Pejler and Allan R. Thomsen^2,*

^* University of Copenhagen, Institute of International Health, Immunology and Microbiology, Copenhagen, Denmark; Department of Medical Biochemistry and Microbiology, Uppsala University, and Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden

We previously reported that the lack of serglycin proteoglycan affects secretory granule morphology and granzyme B (GrB) storage in in vitro generated CTLs. In this study, the role of serglycin during viral infection was studied by infecting wild-type (wt) mice and serglycin-deficient (SG^–/–) mice with lymphocytic choriomeningitis virus (LCMV). Wt and SG^–/– mice cleared 10³ PFU of highly invasive LCMV with the same kinetics, and the CD8⁺ T lymphocytes from wt and SG^–/– animals did not differ in GrB, perforin, IFN-, or TNF- content. However, when a less invasive LCMV strain was used, SG^–/– GrB⁺ CD8⁺ T cells contained 30% less GrB than wt GrB⁺ CD8⁺ T cells. Interestingly, the contraction of the antiviral CD8⁺ T cell response to highly invasive LCMV was markedly delayed in SG^–/– mice, and a delayed contraction of the virus-specific CD8⁺ T cell response was also seen after infection with vesicular stomatitis virus. BrdU labeling of cells in vivo revealed that the delayed contraction was associated with sustained proliferation of Ag-specific CD8⁺ T cells in SG^–/– mice. Moreover, wt LCMV-specific CD8⁺ T cells from TCR318 transgenic mice expanded much more extensively in virus-infected SG^–/– mice than in matched wt mice, indicating that the delayed contraction represents a T cell extrinsic phenomenon. In summary, the present report points to a novel, previously unrecognized role for serglycin proteoglycan in regulating the kinetics of antiviral CD8⁺ T cell responses.

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 in part by the Danish Medical Research Council, the Lundbeck Foundation, and the Novo Nordisk Foundation. M.G. is the recipient of a Postdoctoral Fellowship from the Benzon Foundation.

² Address correspondence and reprint requests to Dr. Allan R. Thomsen, Institute of International Health, Immunology and Microbiology, The Panum Institute Building 22.5, University of Copenhagen, 3C Blegdamsvej, DK-2200 Copenhagen N, Denmark. E-mail address: A.R.Thomsen{at}immi.ku.dk

³ Abbreviations used in this paper: GrB, granzyme B; GrA, granzyme A; LCMV, lymphocytic choriomeningitis virus; VSV, vesicular stomatitis virus; wt, wild type; p.i., postinfection; MFI, mean fluorescence intensity.

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