title: Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection.
abstract: The development of T cell memory from naive precursors is influenced by molecular cues received during T cell activation and differentiation. In this study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8(+) T cell contraction and memory generation after influenza virus infection. We find that Ccr5(-/-) Cxcr3(-/-) cells show markedly decreased contraction after viral clearance, leading to the establishment of massive numbers of memory CD8(+) T cells. Ccr5(-/-) Cxcr3(-/-) cells show reduced expression of CD69 in the lung during the peak of infection, which coincides with differential localization and the rapid appearance of memory precursor cells. Analysis of single chemokine receptor-deficient cells revealed that CXCR3 is primarily responsible for this phenotype, although there is also a role for CCR5 in the enhancement of T cell memory. The phenotype could be reversed by adding exogenous antigen, resulting in the activation and contraction of Ccr5(-/-) Cxcr3(-/-) cells. Similar results were observed during chronic Mycobacterium tuberculosis infection. Together, the data support a model of memory CD8(+) T cell generation in which the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8(+) T cell activation and differentiation, which ultimately regulates effector versus memory cell fate decisions.
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA. jkohlmeier@trudeauinstitute.org
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Kohlmeier
authors.forename: William W
authors.initials: WW
authors.lastname: Reiley
authors.forename: Georgia
authors.initials: G
authors.lastname: Perona-Wright
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Yager
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Connor
authors.forename: Erik L
authors.initials: EL
authors.lastname: Brincks
authors.forename: Tres
authors.initials: T
authors.lastname: Cookenham
authors.forename: Alan D
authors.initials: AD
authors.lastname: Roberts
authors.forename: Claire E
authors.initials: CE
authors.lastname: Burkum
authors.forename: Stewart
authors.initials: S
authors.lastname: Sell
authors.forename: Gary M
authors.initials: GM
authors.lastname: Winslow
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blackman
authors.forename: Markus
authors.initials: M
authors.lastname: Mohrs
authors.forename: David L
authors.initials: DL
authors.lastname: Woodland
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001973:Bromodeoxyuridine; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D019713:Receptors, CCR5 / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D001973:Bromodeoxyuridine