Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals.
The T cell, Ig domain, and mucin domain-1 (TIM-1) gene is associated with Th2 T cell responses and human atopic diseases. The mechanism by which TIM-1 influences T cell responses remains unknown. We demonstrate that TIM-1 is recruited to the TCR-signaling complex via association with CD3. TIM-1 up-regulates TCR-associated signaling events, including phosphorylation of Zap70 and IL-2-inducible T cell kinase. This activity requires TIM-1 tyrosine phosphorylation. TIM-1 expression induces formation of a novel complex that includes PI3K and ITK. Finally, the consequences of TIM-1 activation include increased expression of effector cytokines. These results demonstrate that TIM-1 is a critical component of the human T cell response and provide a mechanistic hypothesis for the role of TIM-1 in disease.
Binné
Lauri L
LL
Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
Scott
Martin L
ML
Rennert
Paul D
PD
D017252:CD3 Complex / Q000032:analysis / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011991:Receptors, Virus / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D017252:CD3 Complex; D016207:Cytokines; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C080813:emt protein-tyrosine kinase