title: Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function.
abstract: It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti-Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-gamma and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti-Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-gamma and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti-Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Jay
authors.initials: J
authors.lastname: Reddy
authors.forename: Monica
authors.initials: M
authors.lastname: Albin
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.forename: Eric
authors.initials: E
authors.lastname: Jensen
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Cristina
authors.initials: C
authors.lastname: Gutierrez
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Terry
authors.initials: T
authors.lastname: Strom
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014162:Transfection
chemical_list: D000906:Antibodies; D017252:CD3 Complex; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma