Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells.
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.
Dardalhon
Valerie
V
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Anderson
Ana C
AC
Karman
Jozsef
J
Apetoh
Lionel
L
Chandwaskar
Rucha
R
Lee
David H
DH
Cornejo
Melanie
M
Nishi
Nozomu
N
Yamauchi
Akira
A
Quintana
Francisco J
FJ
Sobel
Raymond A
RA
Hirashima
Mitsuomi
M
Kuchroo
Vijay K
VK
D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis*; D039481:CD11b Antigen / Q000096:biosynthesis*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D037161:Galectins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016130:Immunophenotyping; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000950:Antigens, Ly; D039481:CD11b Antigen; D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; C480309:Ly6G antigen, mouse; D011991:Receptors, Virus; C508186:galectin 9, mouse