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Control of Memory CD8⁺ T Cell Differentiation by CD80/CD86-CD28 Costimulation and Restoration by IL-2 during the Recall Response¹

Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756

Memory CD8⁺ T cell responses have been considered to be independent of CD80/CD86-CD28 costimulation. However, recall responses are often severely blunted in CD28^–/– mice. Whether this impairment represents a requirement for CD28 costimulation for proper memory CD8⁺ T cell development or a requirement during the recall response is unknown. Furthermore, how CD28 costimulation affects the phenotype and function of memory CD8⁺ T cells has not been characterized in detail. In this study, we investigate these questions by studying the role of the CD28 costimulatory pathway in memory CD8⁺ T cell responses to acute and persistent DNA virus infections. Memory CD8⁺ T cells against vaccinia virus (VV) infection which develop without CD28 costimulation exhibit lower expression of differentiation markers CD27 and CD122 (IL-15Rβ). These memory CD8⁺ T cells also fail to produce IL-2. Our data indicate that for an optimal recall response, CD28 costimulation is required both for T cell priming and also during the recall response. Similar requirements were observed for memory CD8⁺ T cell responses during persistent infection with murine gammaherpesvirus 68 (MHV-68) infection, indicating CD28 may play the same role in both acute and persistent infections. Finally, we show deficits in the recall response are restored by IL-2 signaling during recall, but not during priming. The data presented show that CD28 costimulation not only controls the magnitude of the primary response but also affects development of memory CD8⁺ T cells and is required during the recall response in addition to initial T cell priming.

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 Grant CA103642.

² Address correspondence and reprint requests to Dr. Edward J. Usherwood, Department of Microbiology and Immunology, 1 Medical Center Drive, Darmouth Medical School, Lebanon, NH 03756. E-mail address: edward.j.usherwood{at}dartmouth.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; MHV-68, murine gammaherpesvirus 68; VV-WR, vaccinia virus Western Reserve; i.n., intranasal; rVV, recombinant VV; p.i., postinfection; mIL-2, murine IL-2; BM, bone marrow; R-IgG, rat IgG.

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