title: T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases.
abstract: CD8(+) CTLs are adept at killing virally infected cells and cancer cells and releasing cytokines (e.g., IFN-γ) to aid this response. However, during cancer and chronic viral infections, such as with HIV, this CTL response is progressively impaired due to a process called T cell exhaustion. Previous work has shown that the glycoprotein T cell Ig and mucin domain-containing protein 3 (Tim-3) plays a functional role in establishing T cell exhaustion. Tim-3 is highly upregulated on virus and tumor Ag-specific CD8(+) T cells, and antagonizing Tim-3 helps restore function of CD8(+) T cells. However, very little is known of how Tim-3 signals in CTLs. In this study, we assessed the role of Tim-3 at the immunological synapse as well as its interaction with proximal TCR signaling molecules in primary human CD8(+) T cells. Tim-3 was found within CD8(+) T cell lipid rafts at the immunological synapse. Blocking Tim-3 resulted in a significantly greater number of stable synapses being formed between Tim-3(hi)CD8(+) T cells and target cells, suggesting that Tim-3 plays a functional role in synapse formation. Further, we confirmed that Tim-3 interacts with Lck, but not the phospho-active form of Lck. Finally, Tim-3 colocalizes with receptor phosphatases CD45 and CD148, an interaction that is enhanced in the presence of the Tim-3 ligand, galectin-9. Thus, Tim-3 interacts with multiple signaling molecules at the immunological synapse, and characterizing these interactions could aid in the development of therapeutics to restore Tim-3-mediated immune dysfunction.
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors: Kiera L
authors: KL
authors: Clayton
authors: Matthew S
authors: MS
authors: Haaland
authors: Matthew B
authors: MB
authors: Douglas-Vail
authors: Shariq
authors: S
authors: Mujib
authors: Glen M
authors: GM
authors: Chew
authors: Lishomwa C
authors: LC
authors: Ndhlovu
authors: Mario A
authors: MA
authors: Ostrowski
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D037161:Galectins / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010744:Phosphoric Monoester Hydrolases; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; C486288:PTPRJ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3