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Protection from Lethal Infection by Adoptive Transfer of CD8 T Cells Genetically Engineered to Express Virus-Specific Innate Immune Receptor¹

Koho Iizuka^2,3,*, Chigusa Nakajima^3,, Yoshie-Matsubayashi Iizuka^*, Mitsuyo Takase, Takako Kato, Satoshi Noda, Kazuo Tanaka and Osami Kanagawa^2,

^* Department of Medicine, Center for Immunology and Cancer Center, University of Minnesota, Minneapolis, MN 55455; Laboratory for Autoimmune Regulation, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan; and Laboratory for Infectious Diseases, Tokai University School of Medicine, Isehara, Kanagawa, Japan

CMV infection is one of the most common complications in immunocompromised individuals, such as organ and bone marrow transplant patients. Both innate and adaptive immune responses are required for defense against CMV infection. In murine CMV (MCMV) infection, strains harboring the MCMV-specific NK cell activation receptor, Ly49H (Klra8), are resistant. In contrast, MCMV infection of mice lacking Ly49H gene causes early mortality due to uncontrolled viral replication. In this study, we report the successful protection of mice from lethal MCMV infection with gene-transferred polyclonal CD8 T cells. CD8 T cells expressing a chimeric receptor comprising Ly49H extracellular and CD3 cytoplasmic domains are capable of killing target cells expressing the MCMV protein, m157. CD8 T cells expressing the chimeric receptor protect mice in vivo from lethality in the acute phase of MCMV infection, leading to the establishment of long-term protection. These data provide proof-of-principle evidence that a novel strategy for harnessing CD8 cytolytic function through TCR-independent yet pathogen-specific receptor can result in effective protection of hosts from pathogens.

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 partially supported by National Institutes of Health Grant R21AI064270 (to K.I.) and by American Society of Hematology Scholar Award (to K.I.). K.I.’s laboratory is located in a facility that was constructed with support from Research Facilities Improvement Program Grant Number CO6 CA062526-01 from the National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Koho Iizuka, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: iizuk001{at}umn.edu; or Dr. Osami Kanagawa, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. E-mail address: kanagawa{at}rcai.riken.jp

³ K.I. and C.N. contributed equally to this work.

⁴ Abbreviations used in this paper: DC, Dendritic cell; MCMV, murine CMV; ORF, open reading frame; NKC, NK gene complex; LCR, leukocyte receptor complex; h, human.

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