Peripheral 4-1BB signaling negatively regulates NK cell development through IFN-γ

BK Choi, YH Kim, CH Kim, MS Kim, KH Kim… - The Journal of …, 2010 - journals.aai.org
BK Choi, YH Kim, CH Kim, MS Kim, KH Kim, HS Oh, MJ Lee, DK Lee, DS Vinay, BS Kwon
The Journal of Immunology, 2010journals.aai.org
Abstract 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 …
Abstract
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-γ, which was produced by peripheral CD8+ T and NK cells. The suppression of NK cell development by 4-1BB–mediated IFN-γ 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-γ is critical for this 4-1BB–mediated shift.
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