Peripheral 4-1BB signaling negatively regulates NK cell development through IFN-gamma.
Stimulation of 4-1BB (CD137) was shown to produce strong anticancer effects in vivo. In contrast, 4-1BB-deficient (4-1BB(-/-)) B6 mice are remarkably resistant to tumor growth. We set out to determine the mechanisms involved in these seemingly contradictory observations. We found that the therapeutic effects of 4-1BB triggering were mainly dependent on CD8(+) T cells and partially on NK cells, whereas CD8(+) T and NK cells were equally needed to suppress tumor growth in 4-1BB(-/-) mice. Cellular analysis showed that the frequency and number of NK cells in the spleen and bone marrow were decreased by 4-1BB triggering but were increased in the absence of 4-1BB signaling in tumor-challenged mice. The 4-1BB-mediated downregulation of NK cell development was primarily dependent on IFN-gamma, which was produced by peripheral CD8(+) T and NK cells. The suppression of NK cell development by 4-1BB-mediated IFN-gamma production occurred in the bone marrow. As 4-1BB signaling increased in the periphery, more CD8(+) T cells but fewer NK cells contributed to the antitumor immunity. As 4-1BB signaling decreased, more NK cells participated in the antitumor immunity. We conclude that 4-1BB signaling results in a shift of the dominant type of immune cell in antitumor immunity from the innate NK cell to the adaptive CD8(+) T cell and that the level of IFN-gamma is critical for this 4-1BB-mediated shift.
Choi
Beom K
BK
Division of Cell and Immunobiology, National Cancer Center, 809 Madu, Ilsan, Goyang, Kyounggi-do 411-769, Korea.
Kim
Young H
YH
Kim
Chang H
CH
Kim
Moon S
MS
Kim
Kwang H
KH
Oh
Ho S
HS
Lee
Myoung J
MJ
Lee
Don K
DK
Vinay
Dass S
DS
Kwon
Byoung S
BS
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013945:Thymoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016056:Immunodominant Epitopes; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma