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T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity¹

Violeta Rus^2,*,, Vinh Nguyen^*,, Roman Puliaev, Irina Puliaeva, Valentina Zernetkina^*,, Irina Luzina^*,, John C. Papadimitriou and Charles S. Via

^* Research Service, Department of Veteran Affairs Medical Center, Baltimore, MD 21201; Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, MD 20814

T cells play an essential role in driving humoral autoimmunity in lupus. Molecules such as TRAIL exhibit strong T cell modulatory effects and are up-regulated in lupus, raising the possibility that they may influence disease severity. To address this possibility, we examined the role of TRAIL expression on pathogenic T cells in an induced model of murine lupus, the parent-into-F₁ (PF₁) model of chronic graft-vs-host disease (GVHD), using wild-type or TRAIL-deficient donor T cells. Results were compared with mice undergoing suppressive acute GVHD. Although chronic GVHD mice exhibited less donor T cell TRAIL up-regulation and IFN--inducible gene expression than acute GVHD mice, donor CD4⁺ T cell TRAIL expression in chronic GVHD was essential for sustaining effector CD4⁺ Th cell numbers, for sustaining help to B cells, and for more severe lupus-like renal disease development. Conversely, TRAIL expression on donor CD8⁺ T cells had a milder, but significant down-regulatory effect on CTL effector function, affecting the perforin/granzyme pathway and not the Fas ligand pathway. These results indicate that, in this model, T cell-expressed TRAIL exacerbates lupus by the following: 1) positively regulating CD4⁺ Th cell numbers, thereby sustaining T cell help for B cells, and 2) to a lesser degree by negatively regulating perforin-mediated CD8⁺ CTL killing that could potentially eliminate activated autoreactive B cells.

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 study was supported by National Institutes of Health Grants AI47466 (to C.S.V.) and K23 AR02135-01 (to V.R.), by an Arthritis Foundation Investigator Award (to V.R.), and a Department of Veterans Affairs Merit Review Grant (to C.S.V. and V.R.). R.P. was a recipient of an Engelicheff Fellowship Award from the Maryland Chapter of the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Violeta Rus, University of Maryland School of Medicine, Medical School Teaching Facility, Building, Room 8-34, 10 South Pine Street, Baltimore, MD 21201. E-mail address: vrus{at}umaryland.edu

³ Abbreviations used in this paper: DR, death receptor; FasL, Fas ligand; GVHD, graft-vs-host disease; KO, knockout; MCF, mean channel fluorescence; Mx-1, myxovirus (influenza virus) resistance 1; OAS1a, oligoadenylate synthetase; SLE, systemic lupus erythematosus; WT, wild type; Ct, cycle threshold.

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