title: Activated CD69+ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages.
abstract: 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 (MΦs) 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/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs 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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510 275, People's Republic of China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Li
authors.forename: Tuan-Jie
authors.initials: TJ
authors.lastname: Li
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037181:Lectins, C-Type; D014364:Tryptophan; D000099192:CD69 Antigens