DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction.
It is generally accepted that priming of antitumor CD8+ cytotoxic T lymphocytes (CTLs) needs help that can be provided by CD4+ T cells. We show that interactions between dendritic cells (DCs) and natural killer (NK) cells can bypass the T helper arm in CTL induction. Bone marrow-derived DCs caused rejection of the A20 lymphoma and induced tumor-specific long-term memory, although they were not loaded with tumor-derived antigen. Experiments using CD40(-) knock-out mice and cell depletion showed that this effect did not require CD4+ cells. Both primary rejection and long-term CTL memory were the result of NK cell activation by DCs. NK cytotoxicity, which was necessary for primary rejection, was dependent on expression of natural killer group 2 D (NKG2D) ligands on tumor cells. Blocking of these ligands using NKG2D tetramers abrogated tumor killing in vitro and in vivo. The long-term response was due to CTLs directed against antigen(s) expressed on A20 and in vitro-differentiated DCs. The mechanism leading to CD4+ helper cell-independent CTL responses was elucidated as a cascade that was initiated by NK cell activation. This pathway was dependent on inter-feron-gamma expression and involved priming endogenous DCs for interleukin-12 production. Our data suggest a novel pathway linking innate and adaptive immunity.
Adam
Christian
C
GSF-Institut für Molekulare Immunologie, Marchioninistr. 25, D-81377 München, Germany.
King
Susan
S
Allgeier
Thomas
T
Braumüller
Heidi
H
Lüking
Carolin
C
Mysliwietz
Josef
J
Kriegeskorte
Anja
A
Busch
Dirk H
DH
Röcken
Martin
M
Mocikat
Ralph
R
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D019013:CD40 Antigens; D018664:Interleukin-12; D007371:Interferon-gamma