title: Type 1 IFN mediates cross-talk between innate and adaptive immunity that abrogates transplantation tolerance.
abstract: TLR activation of innate immunity prevents the induction of transplantation tolerance and shortens skin allograft survival in mice treated with costimulation blockade. The mechanism by which TLR signaling mediates this effect has not been clear. We now report that administration of the TLR agonists LPS (TLR4) or polyinosinic:polycytidylic acid (TLR3) to mice treated with costimulation blockade prevents alloreactive CD8(+) T cell deletion, primes alloreactive CTLs, and shortens allograft survival. The TLR4- and MyD88-dependent pathways are required for LPS to shorten allograft survival, whereas polyinosinic:polycytidylic acid mediates its effects through a TLR3-independent pathway. These effects are all mediated by signaling through the type 1 IFN (IFN-alphabeta) receptor. Administration of IFN-beta recapitulates the detrimental effects of TLR agonists on transplantation tolerance. We conclude that the type 1 IFN generated as part of an innate immune response to TLR activation can in turn activate adaptive immune responses that abrogate transplantation tolerance. Blocking of type 1 IFN-dependent pathways in patients may improve allograft survival in the presence of exogenous TLR ligands.
authors.affiliation: Department of Medicine, Division of Diabetes, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thornley
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Phillips
authors.forename: Britte C
authors.initials: BC
authors.lastname: Beaudette-Zlatanova
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Markees
authors.forename: Kapil
authors.initials: K
authors.lastname: Bahl
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rossini
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects; D014184:Transplantation, Homologous
chemical_list: D007369:Interferon Inducers; D007370:Interferon Type I; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D053633:Receptor, Interferon alpha-beta; D011070:Poly I-C