title: Chemokine receptor CXCR3 facilitates CD8(+) T cell differentiation into short-lived effector cells leading to memory degeneration.
abstract: Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8(+) T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8(+) T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3(-/-) antigen-specific CD8(+) T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8(+) T cells. Early after infection, CXCR3(-/-) antigen-specific CD8(+) T cells fail to cluster at the marginal zone in the spleen where inflammatory cytokines such as IL-12 and IFN-α are abundant, thus receiving relatively weak inflammatory stimuli. Consequently, CXCR3(-/-) CD8(+) T cells exhibit transient expression of CD25 and preferentially differentiate into memory precursor effector cells as compared with wild-type CD8(+) T cells. This series of events has important implications for development of vaccination strategies to generate increased numbers of antigen-specific memory CD8(+) T cells via inhibition of CXCR3-mediated T cell migration to inflamed microenvironments.
authors.affiliation: Department of Molecular Preventive Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.forename: Junko
authors.initials: J
authors.lastname: Kurachi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Suenaga
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tsukui
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.forename: Michio
authors.initials: M
authors.lastname: Tomura
authors.forename: Kei
authors.initials: K
authors.lastname: Sugihara
authors.forename: Shiki
authors.initials: S
authors.lastname: Takamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001973:Bromodeoxyuridine; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: C515188:Cxcr3 protein, mouse; D017931:DNA Primers; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D054367:Receptors, CXCR3; D001973:Bromodeoxyuridine