Protection from lethal infection by adoptive transfer of CD8 T cells genetically engineered to express virus-specific innate immune receptor.
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 CD3zeta 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.
Iizuka
Koho
K
Department of Medicine, Center for Immunology and Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. iizuk001@umn.edu
Nakajima
Chigusa
C
Iizuka
Yoshie-Matsubayashi
YM
Takase
Mitsuyo
M
Kato
Takako
T
Noda
Satoshi
S
Tanaka
Kazuo
K
Kanagawa
Osami
O
D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis* / Q000235:genetics; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D002678:Chimera; D006566:Herpesviridae Infections / Q000517:prevention & control*; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology; D055650:NK Cell Lectin-Like Receptor Subfamily A; D016133:Polymerase Chain Reaction; D015202:Protein Engineering / Q000379:methods; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D055630:Receptors, NK Cell Lectin-Like
D000950:Antigens, Ly; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C527096:Klra8 protein, mouse; D037181:Lectins, C-Type; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like