title: Suppression of allograft rejection by Tim-1-Fc through cross-linking with a novel Tim-1 binding partner on T cells.
abstract: Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4(+) effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4(+) T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4(+) T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3(+) cells in splenic CD4(+) T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4(+)CD25(-) T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection.
authors.affiliation: Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.forename: Zhi-ren
authors.initials: ZR
authors.lastname: Fu
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Lu-ding
authors.initials: LD
authors.lastname: Zhang
authors.forename: Xiao-min
authors.initials: XM
authors.lastname: Shi
authors.forename: Xiao-yun
authors.initials: XY
authors.lastname: Shen
authors.forename: Zhi-jia
authors.initials: ZJ
authors.lastname: Ni
authors.forename: Hong
authors.initials: H
authors.lastname: Fu
authors.forename: Rui-dong
authors.initials: RD
authors.lastname: Li
authors.forename: Xue-tao
authors.initials: XT
authors.lastname: Cao
authors.forename: Guo-shan
authors.initials: GS
authors.lastname: Ding
authors.forename: Quan-xing
authors.initials: QX
authors.lastname: Wang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D007141:Immunoglobulin Fc Fragments; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3