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Tim-3/Galectin-9 Pathway: Regulation of Th1 Immunity through Promotion of CD11b+Ly-6G+ Myeloid Cells

2010; American Association of Immunologists; Volume: 185; Issue: 3 Linguagem: Inglês

10.4049/jimmunol.0903275

1550-6606

Valérie Dardalhon, Ana C. Anderson, József Kármán, Lionel Apétoh, Rucha Chandwaskar, David H. Lee, Melanie Cornejo, Nozomu Nishi, Akira Yamauchi, Francisco J. Quintana, Raymond A. Sobel, Mitsuomi Hirashima, Vijay K. Kuchroo,

Signaling Pathways in Disease

IFN-gamma plays a central role in antitumor immunity. T cell Ig and mucin domain (Tim-3) is expressed on IFN-gamma-producing Th1 cells; on interaction with its ligand, galectin-9, Th1 immunity is terminated. In this study, we show that transgenic overexpression of Tim-3 on T cells results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Molecular characterization of CD11b(+)Ly-6G(+) cells reveals a phenotype consistent with granulocytic myeloid-derived suppressor cells. Accordingly, we find that modulation of the Tim-3/galectin-9 (Gal-9) pathway impacts on tumor growth. Similarly, overexpression of Tim-3 ligand, Gal-9, results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Loss of Tim-3 restores normal levels of CD11b(+)Ly-6G(+) cells and normal immune responses in Gal-9 transgenic mice. Our data uncover a novel mechanism by which the Tim-3/Gal-9 pathway regulates immune responses and identifies this pathway as a therapeutic target in diseases where myeloid-derived suppressor cells are disadvantageous.