{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:52:29Z","timestamp":1790887949457,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2010,8,1]],"date-time":"2010-08-01T00:00:00Z","timestamp":1280620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Stimulation of 4-1BB (CD137) was shown to produce strong anticancer effects in vivo. In contrast, 4-1BB\u2013deficient (4-1BB\u2212\/\u2212) 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\u2212\/\u2212 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\u2013mediated downregulation of NK cell development was primarily dependent on IFN-\u03b3, which was produced by peripheral CD8+ T and NK cells. The suppression of NK cell development by 4-1BB\u2013mediated IFN-\u03b3 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-\u03b3 is critical for this 4-1BB\u2013mediated shift.<\/jats:p>","DOI":"10.4049\/jimmunol.1000850","type":"journal-article","created":{"date-parts":[[2010,7,8]],"date-time":"2010-07-08T03:12:48Z","timestamp":1278558768000},"page":"1404-1411","source":"Crossref","is-referenced-by-count":31,"title":["Peripheral 4-1BB Signaling Negatively Regulates NK Cell Development through IFN-\u03b3"],"prefix":"10.1093","volume":"185","author":[{"given":"Beom K","family":"Choi","sequence":"first","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young H","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang H","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon S","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang H","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho S","family":"Oh","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung J","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don K","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dass S","family":"Vinay","sequence":"additional","affiliation":[{"name":"Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center , New Orleans, LA 70118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byoung S","family":"Kwon","sequence":"additional","affiliation":[{"name":"Division of Cell and Immunobiology, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"R&D Center for Cancer Therapeutics, National Cancer Center , Goyang, Kyeonggi-do ,","place":["Korea"]},{"name":"Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center , New Orleans, LA 70118"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,8,1]]},"reference":[{"key":"2025032411423174700_r1","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.4049\/jimmunol.155.7.3360","article-title":"Potential role of 4-1BB in T cell activation. 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