title: Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.
abstract: Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
authors.forename: Li-Rung
authors.initials: LR
authors.lastname: Huang
authors.forename: Dirk
authors.initials: D
authors.lastname: Wohlleber
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.forename: Craig N
authors.initials: CN
authors.lastname: Jenne
authors.forename: Ru-Lin
authors.initials: RL
authors.lastname: Cheng
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdullah
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Dienes
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002908:Chronic Disease; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D007167:Immunotherapy; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008107:Liver Diseases / Q000276:immunology* / Q000628:therapy / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000628:therapy / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D053262:Receptors, OX40; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D049452:Green Fluorescent Proteins