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Tumor‐educated tolerogenic dendritic cells induce downregulation of CD3ε and apoptosis in T cells via an oxygen‐dependent pathway
Author(s) -
Kuang DongMing,
Wu Changyou,
Zheng Limin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1076.13
Subject(s) - cd3 , microbiology and biotechnology , t cell , immune system , biology , nadph oxidase , t cell receptor , downregulation and upregulation , cancer research , immunology , chemistry , reactive oxygen species , cd8 , biochemistry , gene
Defects in the CD3/TCR complex and impairment of T cell function are necessary for evasion of tumor, but the underlying mechanisms are incompletely understood. We found that culture supernatants from several types of solid tumor cells drived human monocytes to become tolerogenic semimature dendritic cells (TDCs). Upon encountering T cells, the TDCs triggered rapid down‐regulation of CD3ε and TCR‐α/β and subsequent apoptosis in autologous T cells. Consistent with these results, accumulation of immunosuppressive DCs coincided with CD3ε down‐regulation and T cell deletion in cancer nests of human tumors. The impaired T cell function was mediated by factor(s) released by live TDCs after direct interaction with lymphocytes. Also, the TDC‐induced effect on T cells was markedly reduced by blocking of NADPH oxidase but not by inhibition of arginase, iNOS, indoleamine 2,3‐dioxygenase (IDO), or IFN‐γ. Moreover, we found that hyaluronan fragments constituted a common factor produced by a variety of human tumors to induce formation of TDCs. These observations indicate that tumor microenvironments, including hyaluronan fragments derived from cancer cells, educate DCs to adopt a semimature phenotype, which in turn aids tumor immune escape by causing defects in the CD3/TCR complex and deletion of T cells.