title: Immunoregulation of dendritic cells by the receptor T cell Ig and mucin protein-3 via Bruton's tyrosine kinase and c-Src.
abstract: The receptor T cell Ig and mucin protein-3 (TIM-3) has emerged as an important regulator of innate immune responses. However, whether TIM-3-induced signaling promotes or inhibits the activation and maturation of dendritic cells (DCs) still remains uncertain. In addition, the TIM-3 signaling events involved in this immunoregulatory function are yet to be established. In this article, we report that TIM-3 crosslinking by anti-TIM-3 Ab inhibited DC activation and maturation by blocking the NF-κB pathway. After Ab-mediated crosslinking, TIM-3 became tyrosine phosphorylated, which then sequentially bound and activated the nonreceptor tyrosine kinases Bruton's tyrosine kinase (Btk) and c-Src. Activation of Btk-c-Src signaling in turn triggered the secretion of some inhibitory factor (or factors) from DCs that inhibited the NF-κB pathway and subsequent activation and maturation of DCs. Silencing of Btk or c-Src abrogated the inhibitory effects of TIM-3 on DCs. These results demonstrate an essential role for Btk-c-Src signaling in TIM-3-induced DC suppression. Thus, in addition to demonstrating an inhibitory role for TIM-3 signaling in DC activation, we define the molecular mechanism by which TIM-3 mediates this effect.
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Maurya
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Gujar
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Verma
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India psen@imtech.res.in.
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D020868:Gene Silencing; D000072597:Hepatitis A Virus Cellular Receptor 2; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D016328:NF-kappa B; D011991:Receptors, Virus; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases