title: Dendritic cells treated with lipopolysaccharide up-regulate serine protease inhibitor 6 and remain sensitive to killing by cytotoxic T lymphocytes in vivo.
abstract: Ag presentation by dendritic cells (DC) in vivo is essential to the initiation of primary and secondary T cell responses. We have reported that DC presenting Ag in the context of MHC I molecules also become targets of specific CTL and are rapidly killed in mice. However, activated DC up-regulate expression of serine protease inhibitor (SPI)-6, a specific blocker of the cytotoxic granule protein granzyme B, which modulates their susceptibility to CTL-mediated killing in vitro. We wanted to determine whether susceptibility to CTL-mediated killing in vivo is also modulated by DC activation. As was previously reported by others, DC treated with different doses of LPS expressed higher levels of SPI-6 mRNA than did untreated DC. The increased expression of SPI-6 was functionally relevant, as LPS-treated DC became less susceptible to CTL-mediated killing in vitro. However, when these LPS-treated DC were injected in vivo, they remained sensitive to CTL-mediated killing regardless of whether the CTL activity was elicited in host mice via active immunization or was passively transferred via injection of in vitro-activated CTL. LPS-treated DC were also sensitive to killing in lymph node during the reactivation of memory CTL. We conclude that increased SPI-6 expression is not sufficient to confer DC with resistance to direct killing in vivo. However, SPI-6 expression may provide DC with a survival advantage in some conditions, such as those modeled by in vitro cytotoxicity assays.
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Andrew
authors.forename: Helen M A
authors.initials: HM
authors.lastname: Simkins
authors.forename: Sabine
authors.initials: S
authors.lastname: Witzel
authors.forename: Rachel
authors.initials: R
authors.lastname: Perret
authors.forename: Jenny
authors.initials: J
authors.lastname: Hudson
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
authors.forename: Jianping
authors.initials: J
authors.lastname: Yang
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
mesh_terms: D000818:Animals; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology* / Q000637:transplantation; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015843:Serpins; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse