{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:27:19Z","timestamp":1791268039908,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2012,2,1]],"date-time":"2012-02-01T00:00:00Z","timestamp":1328054400000},"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":[[2012,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69+ T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69+ T cells, tumor macrophages (M\u03a6s) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69+ T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes\/M\u03a6s isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor M\u03a6s was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO+ M\u03a6s effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating M\u03a6s with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.<\/jats:p>","DOI":"10.4049\/jimmunol.1100164","type":"journal-article","created":{"date-parts":[[2011,12,20]],"date-time":"2011-12-20T04:48:46Z","timestamp":1324356526000},"page":"1117-1124","source":"Crossref","is-referenced-by-count":152,"title":["Activated CD69+ T Cells Foster Immune Privilege by Regulating IDO Expression in Tumor-Associated Macrophages"],"prefix":"10.1093","volume":"188","author":[{"given":"Qiyi","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]},{"name":"Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ming","family":"Kuang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan-Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510 275 ,","place":["People\u2019s Republic of China"]},{"name":"State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center , Guangzhou 210 275 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,2,1]]},"reference":[{"key":"2025032409471801500_r1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/nrc1477","article-title":"Friends or foes - bipolar effects of the tumour stroma in cancer","volume":"4","author":"Mueller","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2025032409471801500_r2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.pathol.1.110304.100224","article-title":"Tumor stroma and regulation of cancer development","volume":"1","author":"Tlsty","year":"2006","journal-title":"Annu. Rev. Pathol."},{"key":"2025032409471801500_r3","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.jhep.2010.08.041","article-title":"Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma","volume":"54","author":"Kuang","year":"2011","journal-title":"J. Hepatol."},{"key":"2025032409471801500_r4","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/nrc2444","article-title":"The role of myeloid cells in the promotion of tumour angiogenesis","volume":"8","author":"Murdoch","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"2025032409471801500_r5","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/hep.23291","article-title":"Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells","volume":"51","author":"Kuang","year":"2010","journal-title":"Hepatology"},{"key":"2025032409471801500_r6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccr.2009.06.018","article-title":"CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages","volume":"16","author":"DeNardo","year":"2009","journal-title":"Cancer Cell"},{"key":"2025032409471801500_r7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.4049\/jimmunol.177.1.40","article-title":"Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells","volume":"177","author":"Kryczek","year":"2006","journal-title":"J. Immunol."},{"key":"2025032409471801500_r8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/hep.23273","article-title":"Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B","volume":"51","author":"Zhang","year":"2010","journal-title":"Hepatology"},{"key":"2025032409471801500_r9","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/nm1633","article-title":"Adaptive immune cells temper initial innate responses","volume":"13","author":"Kim","year":"2007","journal-title":"Nat. Med."},{"key":"2025032409471801500_r10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.it.2008.10.003","article-title":"Do adaptive immune cells suppress or activate innate immunity?","volume":"30","author":"Zhao","year":"2009","journal-title":"Trends Immunol."},{"key":"2025032409471801500_r11","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nrc1256","article-title":"Tumour-educated macrophages promote tumour progression and metastasis","volume":"4","author":"Pollard","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2025032409471801500_r12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cell.2010.03.014","article-title":"Macrophage diversity enhances tumor progression and metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"2025032409471801500_r13","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/nri1733","article-title":"Monocyte and macrophage heterogeneity","volume":"5","author":"Gordon","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409471801500_r14","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1182\/blood-2007-01-068031","article-title":"Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes","volume":"110","author":"Kuang","year":"2007","journal-title":"Blood"},{"key":"2025032409471801500_r15","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1084\/jem.20082173","article-title":"Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1","volume":"206","author":"Kuang","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025032409471801500_r16","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1002\/eji.201041282","article-title":"Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients","volume":"41","author":"Zhao","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025032409471801500_r17","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.it.2004.12.006","article-title":"CD69 is an immunoregulatory molecule induced following activation","volume":"26","author":"Sancho","year":"2005","journal-title":"Trends Immunol."},{"key":"2025032409471801500_r18","doi-asserted-by":"crossref","first-page":"6983","DOI":"10.4049\/jimmunol.177.10.6983","article-title":"CD4+CXCR4highCD69+ T cells accumulate in lung adenocarcinoma","volume":"177","author":"Wald","year":"2006","journal-title":"J. Immunol."},{"key":"2025032409471801500_r19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4049\/jimmunol.182.1.111","article-title":"CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1","volume":"182","author":"Han","year":"2009","journal-title":"J. Immunol."},{"key":"2025032409471801500_r20","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nri1457","article-title":"IDO expression by dendritic cells: tolerance and tryptophan catabolism","volume":"4","author":"Mellor","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409471801500_r21","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.it.2005.12.006","article-title":"The immunoregulatory role of IDO-producing human dendritic cells revisited","volume":"27","author":"Terness","year":"2006","journal-title":"Trends Immunol."},{"key":"2025032409471801500_r22","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/nm934","article-title":"Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase","volume":"9","author":"Uyttenhove","year":"2003","journal-title":"Nat. Med."},{"key":"2025032409471801500_r23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/cmi.2010.53","article-title":"Indoleamine 2,3-dioxygenase and regulatory dendritic cells contribute to the allograft protection induced by infusion of donor-specific splenic stromal cells","volume":"8","author":"Liu","year":"2011","journal-title":"Cell. Mol. Immunol."},{"key":"2025032409471801500_r24","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nature06471","article-title":"Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease","volume":"451","author":"Romani","year":"2008","journal-title":"Nature"},{"key":"2025032409471801500_r25","doi-asserted-by":"crossref","first-page":"7752","DOI":"10.4049\/jimmunol.0901004","article-title":"Human activated T lymphocytes modulate IDO expression in tumors through Th1\/Th2 balance","volume":"183","author":"Godin-Ethier","year":"2009","journal-title":"J. Immunol."},{"key":"2025032409471801500_r26","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1182\/blood-2005-06-2399","article-title":"IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients","volume":"107","author":"Ahmadzadeh","year":"2006","journal-title":"Blood"},{"key":"2025032409471801500_r27","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ab.2005.10.039","article-title":"A fluorescence-based assay for indoleamine 2,3-dioxygenase","volume":"349","author":"Matin","year":"2006","journal-title":"Anal. Biochem."},{"key":"2025032409471801500_r28","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1172\/JCI31911","article-title":"Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase","volume":"117","author":"Sharma","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025032409471801500_r29","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1084\/jem.189.9.1363","article-title":"Inhibition of T cell proliferation by macrophage tryptophan catabolism","volume":"189","author":"Munn","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025032409471801500_r30","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev.immunol.25.022106.141609","article-title":"Immunosuppressive strategies that are mediated by tumor cells","volume":"25","author":"Rabinovich","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2025032409471801500_r31","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1038\/ni1003","article-title":"Modulation of tryptophan catabolism by regulatory T cells","volume":"4","author":"Fallarino","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032409471801500_r32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nri2233","article-title":"Creating immune privilege: active local suppression that benefits friends, but protects foes","volume":"8","author":"Mellor","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409471801500_r33","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1084\/jem.20021337","article-title":"Enhanced antitumor immunity in mice deficient in CD69","volume":"197","author":"Esplugues","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025032409471801500_r34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1172\/JCI200319112","article-title":"CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis","volume":"112","author":"Sancho","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2025032409471801500_r35","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/1521-4141(200002)30:2<644::AID-IMMU644>3.0.CO;2-H","article-title":"CD69-triggered ERK activation and functions are negatively regulated by CD94 \/ NKG2-A inhibitory receptor","volume":"30","author":"Zingoni","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"2025032409471801500_r36","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.4049\/jimmunol.0904094","article-title":"Tumor-activated monocytes promote expansion of IL-17-producing CD8+ T cells in hepatocellular carcinoma patients","volume":"185","author":"Kuang","year":"2010","journal-title":"J. Immunol."},{"key":"2025032409471801500_r37","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","article-title":"Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes","volume":"23","author":"Mantovani","year":"2002","journal-title":"Trends Immunol."},{"key":"2025032409471801500_r38","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.4049\/jimmunol.180.4.2011","article-title":"Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms","volume":"180","author":"Biswas","year":"2008","journal-title":"J. Immunol."},{"key":"2025032409471801500_r39","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.humpath.2008.08.011","article-title":"High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection","volume":"40","author":"Ding","year":"2009","journal-title":"Hum. Pathol."},{"key":"2025032409471801500_r40","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1158\/0008-5472.CAN-09-3170","article-title":"Central role of IFNgamma-indoleamine 2,3-dioxygenase axis in regulation of interleukin-12-mediated antitumor immunity","volume":"70","author":"Gu","year":"2010","journal-title":"Cancer Res."},{"key":"2025032409471801500_r41","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/nm1196","article-title":"Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy","volume":"11","author":"Muller","year":"2005","journal-title":"Nat. Med."},{"key":"2025032409471801500_r42","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1172\/JCI19210","article-title":"Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection","volume":"113","author":"Subudhi","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2025032409471801500_r43","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nri2326","article-title":"Inhibitory B7-family molecules in the tumour microenvironment","volume":"8","author":"Zou","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409471801500_r44","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/path.2947","article-title":"Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4\/PI3K activation loop","volume":"225","author":"Wu","year":"2011","journal-title":"J. Pathol."},{"key":"2025032409471801500_r45","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/3\/1117\/62479854\/1100164.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/3\/1117\/62479854\/1100164.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T13:50:44Z","timestamp":1743083444000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/188\/3\/1117\/7979416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,1]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,2,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1100164","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,2]]},"published":{"date-parts":[[2012,2,1]]}}}