Dendritic cells treated with lipopolysaccharide up-regulate serine protease inhibitor 6 and remain sensitive to killing by cytotoxic T lymphocytes in vivo.
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.
Andrew
Kate A
KA
Malaghan Institute of Medical Research, Wellington, New Zealand.
Simkins
Helen M A
HM
Witzel
Sabine
S
Perret
Rachel
R
Hudson
Jenny
J
Hermans
Ian F
IF
Ritchie
David S
DS
Yang
Jianping
J
Ronchese
Franca
F
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*
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015843:Serpins; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse