Soluble Form of T Cell Ig Mucin 3 Is an Inhibitory Molecule in T Cell-Mediated Immune Response

• Published in: Journal of Immunology 2006-02, Vol.176 (3), p.1411-1420
• Main Authors: Geng, Hui, Zhang, Gui-Mei, Li, Dong, Zhang, Hui, Yuan, Ye, Zhu, Han-Gang, Xiao, Han, Han, Ling-Fei, Feng, Zuo-Hua
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Down-Regulation - immunology; Female; Hepatitis A Virus Cellular Receptor 2; Ligands; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organ Specificity - immunology; Protein Binding - immunology; Receptors, Virus - biosynthesis; Receptors, Virus - genetics; Receptors, Virus - metabolism; Receptors, Virus - physiology; RNA, Messenger - metabolism; Solubility; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.3.1411

T cell Ig mucin 3 (Tim-3) has been found to play an important role in Th1-mediated auto- and alloimmune responses, but the function of soluble form of Tim-3 (sTim-3) remains to be elucidated. In this study, we report the inhibitory effect of sTim-3 on T cell-mediated immune response. In this study, sTim-3 mRNA was found, among different tissues and organs, only in splenic cells, and the activation of splenocytes resulted in up-regulated production of both sTim-3 mRNA and protein. We constructed a eukaryotic expression plasmid, psTim-3, which expresses functional murine sTim-3. In C57BL/6 mice inoculated with B16F1 melanoma cells, the growth of tumor was facilitated by the expression of this plasmid in vivo. Furthermore, sTim-3 inhibited the responses of T cells to Ag-specific stimulation or anti-CD3 mAb plus anti-CD28 mAb costimulation and the production of cytokines IL-2 and IFN-gamma in vitro. In tumor rejection model, sTim-3 significantly impaired T cell antitumor immunity, evidenced by decreased antitumor CTL activity and reduced amount of tumor-infiltrating lymphocytes in tumor. Real-time PCR analysis of gene expression in tumor microenvironment revealed the decreased expression of Th1 cytokine genes and the unchanged profile of the genes related to T regulatory cell function, suggesting that the inhibitory effect of sTim-3 on the generation of Ag-specific T cells in vivo is dominated by T effector cells rather than T regulatory cells. Our studies thus define sTim-3 as an immunoregulatory molecule that may be involved in the negative regulation of T cell-mediated immune response.