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OX40 Costimulation Promotes Persistence of Cytomegalovirus-Specific CD8 T Cells: A CD4-Dependent Mechanism¹

Ian R. Humphreys^*, Andrea Loewendorf^*, Carl de Trez^*, Kirsten Schneider^*, Chris A. Benedict^*, Michael W. Munks, Carl F. Ware^2,* and Michael Croft^2,*

^* Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206

The mechanisms that regulate CMV-specific T cell responses in vivo are poorly understood. During murine CMV infection of B6 mice, primary responses in the spleen are dominated by CD8 T cells reactive with antigenic epitopes in M45, M57, and m139 murine CMV gene products. However, during the later persistent phase of infection, CD8 T cell responses to epitopes in m139 and M38 viral gene products predominate. The basis for this shift in CD8 T populations is unknown. In this study, we demonstrate that OX40, a TNFR superfamily member, specifically regulates the accumulation of CD8 T cells reactive with the persistent-phase epitopes. Defective CD8 T cell responses in OX40^–/– mice were replicated in MHC class II^–/– mice implying that CD4 T cells in part controlled the differentiation of the CD8 T cell clones responsive to these epitopes during persistent infection. Furthermore, treatment of infected mice with an agonist OX40 Ab induced expansion of protective primary virus-specific CD8 T cells independent of CD4 T cell help, but CD4 T cells were crucial for anti-OX40 to promote CD8 T cells reactive to the persistent dominant epitopes. Collectively, these results indicate manipulation of OX40 may be useful in improving cellular immunotherapy regimes for treatment of persistent virus infections.

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 National Institutes of Health Grants CA91837 and AI67341 (to M.C.), AI048073, AI057840, AI057840, and R37AI33068 (to C.F.W.). A.L. is supported by Deutsche Forschungsgemeinschaft Fellowship LO1421/1-1.

² Address correspondence and reprint requests to Dr. Michael Croft, Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037; E-mail address: mick{at}liai.org or Dr. Carl F. Ware, Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037; E-mail address: cware{at}liai.org

³ Abbreviations used in this paper: HCMV, human CMV; MCMV, murine CMV; OX40L, OX40 ligand; LCMV, lymphocytic choriomeningitis virus; VSV, vesicular stomatitis virus.

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