title: Infection of adult thymus with murine retrovirus induces virus-specific central tolerance that prevents functional memory CD8+ T cell differentiation.
abstract: In chronic viral infections, persistent antigen presentation causes progressive exhaustion of virus-specific CD8+ T cells. It has become clear, however, that virus-specific naïve CD8+ T cells newly generated from the thymus can be primed with persisting antigens. In the setting of low antigen density and resolved inflammation, newly primed CD8+ T cells are preferentially recruited into the functional memory pool. Thus, continual recruitment of naïve CD8+ T cells from the thymus is important for preserving the population of functional memory CD8+ T cells in chronically infected animals. Friend virus (FV) is the pathogenic murine retrovirus that establishes chronic infection in adult mice, which is bolstered by the profound exhaustion of virus-specific CD8+ T cells induced during the early phase of infection. Here we show an additional evasion strategy in which FV disseminates efficiently into the thymus, ultimately leading to clonal deletion of thymocytes that are reactive to FV antigens. Owing to the resultant lack of virus-specific recent thymic emigrants, along with the above exhaustion of antigen-experienced peripheral CD8+ T cells, mice chronically infected with FV fail to establish a functional virus-specific CD8+ T cell pool, and are highly susceptible to challenge with tumor cells expressing FV-encoded antigen. However, FV-specific naïve CD8+ T cells generated in uninfected mice can be primed and differentiate into functional memory CD8+ T cells upon their transfer into chronically infected animals. These findings indicate that virus-induced central tolerance that develops during the chronic phase of infection accelerates the accumulation of dysfunctional memory CD8+ T cells.
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Shiki
authors.initials: S
authors.lastname: Takamura
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kajiwara
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Tsuji-Kawahara
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Masumoto
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Chikaishi
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Kinoshita
authors.affiliation: Department of Immunology and Microbiology, Meiji University of Integrative Medicine, Kyoto, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Itoi
authors.affiliation: Department of Immunology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
authors.affiliation: Department of Immunology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
mesh_terms: D000375:Aging; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D005622:Friend murine leukemia virus / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012192:Retroviridae Infections / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology / Q000821:virology*