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Recall Responses by Helpless Memory CD8⁺ T Cells Are Restricted by the Up-Regulation of PD-1¹

Shinichiro Fuse^*, Ching-Yi Tsai^*, Michael J. Molloy^*, S. Rameeza Allie^*, Weijun Zhang^*, Hideo Yagita and Edward J. Usherwood^2,*

^* Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

CD4 help is crucial for memory CD8⁺ T cell development, yet the mechanisms of CD4 help and why (CD4) helpless memory CD8⁺ T cells elicit poor recall responses are currently not well understood. In this study we investigated these questions using an in vivo acute virus infection model. We show herein that CD4 help during priming is required for memory CD8⁺ T cell differentiation, and that stimulation of CD40 during priming rescues the helpless defects in the absence of CD4⁺ T cells. The defective recall response by helpless memory cells did not correlate with the amount of cell death and was independent of TRAIL. However, helpless memory cells excessively up-regulated the inhibitory receptor PD-1 (programmed cell death-1), and PD-1 blockade enhanced the recall response of helpless memory cells. Furthermore, providing IL-2 signaling in vivo during the recall response reduced PD-1 expression and rescued the recall response of helpless memory cells. Our study identifies molecular pathways involved in CD4 help for memory CD8⁺ T cell generation that are independent of TRAIL, and it provides therapeutic implications that helpless memory cell function can be restored at multiple stages through various immunological interventions.

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, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address: edward.j.usherwood{at}dartmouth.edu

³ Abbreviations used in this paper: DC, dendritic cell; i.n., intranasal; MHV-68, murine gammaherpesvirus-68; MFI, mean fluorescence intensity; ORF, open reading frame; PD-1, programmed cell death-1; p.i., postinfection; R-IgG, rat IgG; VLP, virus-like particle; VV, vaccinia virus; VV-WR, vaccinia virus Western Reserve strain.