title: Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells.
abstract: We show that the T-cell immunoglobalin mucin, Tim-1, initially reported to be expressed on CD4(+) T cells, is constitutively expressed on dendritic cells (DCs) and that its expression further increases after DC maturation. Tim-1 signaling into DCs upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T-cell responses, while inhibiting Foxp3(+) Treg responses. By contrast, Tim-1 signaling in T cells only regulates Th2 responses. Using a high-avidity/agonistic anti-Tim-1 antibody as a co-adjuvant enhances the immunogenic function of DCs, decreases the suppressive function of Tregs, and substantially increases proinflammatory Th17 responses in vivo. The treatment with high- but not low-avidity anti-Tim-1 not only worsens experimental autoimmune encephalomyelitis (EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim-1 has an important role in regulating DC function and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim-1 regulates DC and T-cell responses, we may clarify the potential utility of Tim-1 as a target of therapy against autoimmunity, cancer, and infectious diseases.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Hulin
authors.initials: H
authors.lastname: Jin
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D007114:Immunization; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058408:Th1-Th2 Balance
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C435023:myelin proteolipid protein (139-151)