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Extent of Stimulation Controls the Formation of Memory CD8 T Cells¹

Michael Quigley, Xiaopei Huang^* and Yiping Yang^2,*,

^* Department of Medicine, Division of Medical Oncology, and Department of Immunology, Duke University Medical Center, Durham, NC 27710

Only a small fraction of effector CD8 T cells survives to become long-lived memory cells, whereas the majority of them die after an acute infection. What controls the formation of memory CD8 T cells remains mostly unknown. In this study, we showed CD8 T cells primed earlier during vaccinia viral infection received stronger stimulation, divided more extensively, and survived better than those primed later, leading to generation of a larger memory pool. Despite differentiation into effectors, the late-primed CD8 T cells lacked full cell division, displayed increased apoptosis, and failed to develop into memory cells, suggesting that the extent of stimulation influences the survival of effector CD8 T cells. We further demonstrated that the extent of stimulation, which included both the duration and the levels of antigenic stimulation/costimulation, during priming determined the formation of memory CD8 T cells via controlling the extent of Akt activation, and functional suppression of Akt led to defective CD8 memory formation in vivo. Collectively, our data suggest that the extent of stimulation controls CD8 memory formation via activation of Akt and may provide important insights into the design of effective vaccines.

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 CA111807 and CA047741 (to Y.Y.) and an Alliance for Cancer Gene Therapy grant (to Y.Y.).

² Address correspondence and reprint requests to Dr. Yiping Yang, Departments of Medicine and Immunology, Duke University Medical Center, Box 103005, Durham, NC 27710. E-mail address: yang0029{at}mc.duke.edu

³ Abbreviations used in this paper: HA, hemagglutinin; Ad-HA, adenovirus encoding HA; DC, dendritic cell; dn-Akt, dominant-negative Akt; rVV-HA, recombinant vaccinia virus encoding HA.

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