|Title:||Up-Regulation of Inhibitory Natural Killer Receptors Cd94/Nkg2a with Suppressed Intracellular Perforin Expression of Tumor-Infiltrating Cd8+ T Lymphocytes in Human Cervical Carcinoma||Authors:||SHEU, BOR-CHING
|Keywords:||human;T lymphocyte;NK receptor;tumor immunology;perforin||Issue Date:||2005||Journal Volume:||v.65||Journal Issue:||n.7||Start page/Pages:||2921-2929||Source:||CANCER RESEARCH||Abstract:||
Inhibitory signals that govern the cytolytic functions of CD 8+ T lymphocytes have been linked to the expression of natural killer cell receptors (NKRs) on CTLs. There is limited knowledge about the induction of inhibitory NKR ( iNKR) expression in vivo. Up-regulation of iNKRs has been linked to the modulation of the virus- and/or tumor-specific immune responses in animal models. In the present study, we directly examined the expression of various NKRs on tumor- infiltrating lymphocytes (TILs) derived from human cervical cancer. We found that in human cervical cancer , the percentage expression of immunoglobulin-like NKR+CD8+ T lymphocytes were similar in gated CD8+-autologous TILs and peripheral blood mononuclear cells. On the contrary, cervical cancer–infiltrating CD8+ T lymphocytes expressed up-regulated C-type lectin NKRs CD94/NKG2A compared with either peripheral blood CD8+ T cells or normal cervix- infiltrating CD8+ T lymphocytes. Dual NKR coexpression analyses showed that CD94 and NKG2A were mainly expressed on CD56–CD161–CD8+ TILs within the cancer milieu. Immunohistochemical study showed that cervical cancer cells expressed abundant interleukin 15 (IL-15) and transforming growth factor-& szlig; (TGF-ß). In kinetic coculture assay, cervical cancer cells can promote the expression of CD94/NKG2A on CD8+ T lymphocytes. The cancer -derived effects can be reversed by addition of rIL-15R/Fc and anti–TGF- szlig; antibody. Functional analyses illustrated that intracellular perforin expression of CD8+ T cells was minimal upon up-regulation of CD94 /NKG2A. Kinetic cytotoxicity assays showed that up-regulated expressions of CD94/NKG2A restrain CD8+ T lymphocyte cytotoxicity. Our study strongly indicated that cervical cancer cells could promote the expression of iNKRs via an IL-15– and possibly TGF-ß–mediated mechanism and abrogate the antitumor cytotoxicity of TILs.
|Appears in Collections:||醫學系|
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