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Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8⁺ T Cell Exhaustion¹

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129

The failure of CD8⁺ T cells to respond to chronic infection has been termed "exhaustion" and describes the condition in which CD8⁺ T cells exhibit reduced differentiation, proliferation, and effector function. CD8⁺ T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8⁺ T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8⁺ T cell impairment, that Ag-driven loss of virus-specific CD8⁺ T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8⁺ T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8⁺ T cells in chronic infection.

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 R01 AI62437, AI46719, and AI66215 awarded by the National Institutes of Health (to P.D.K.).

² Address correspondence and reprint requests to Dr. Peter D. Katsikis, Department of Microbiology and Immunology, and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address: Peter.Katsikis{at}DrexelMed.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; DC, dendritic cell; i.n., intranasal; NP, nuclear protein; MLN, mediastinal lymph node; MFI, mean fluorescence intensity; TCID₅₀, 50% tissue culture infective dose; Tg, transgenic; PD-1, programmed death 1; PD-L1, programmed death ligand 1.