International Immunology Advance Access originally published online on February 15, 2006
International Immunology 2006 18(3):473-484; doi:10.1093/intimm/dxh388
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Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins
1 CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA
2 Bolder BioPATH Inc., Boulder, CO, USA
3 Present address: Celera Genomics, 45 West Gude Drive, Rockville, MD 20850, USA
4 Present address: 675 North Field Drive, Lake Forest, IL 60045, USA
5 Present address: PDL Bio Pharma, 34801 Campus Drive, Fremont, CA 94555, USA
Correspondence to: G. Smithson; E-mail: info{at}curagen.com
Members of the T cell, Ig domain and mucin domain (Tim) family of proteins have recently been implicated in the control of T cell-mediated immune responses. Tim-1 (HUGO designation HAVCR1) polymorphisms have been linked to the regulation of atopy in mice and humans, suggestive of a role in immune regulation. Tim-1 is expressed upon activation of T cells. In concert with the increased expression of Tim-1, a binding partner for the extracellular domain of Tim-1 (eTim-1) was induced on activated T cells, and mRNA expression data was consistent with the binding partner being Tim-4. We found that co-immobilized recombinant eTim-1 was able to inhibit T cell activation mediated by CD3 + CD28 mAb. eTim-1 mediated its inhibitory effects on proliferation by arresting cell cycle at G0/G1 phase through regulation of cell cycle proteins. In vivo, administration of eTim-1 proteins led to a decrease in both ear (contact hypersensitivity to oxazolone) and joint (methylated BSA antigen-induced arthritis) swelling. The inhibitory activity of eTim-1 in the Th1-dependent models was evidence that eTim-1 is able to modulate T cell responses. Manipulation of the Tim-1 interaction with its binding partner on T cells may therefore provide a novel target for therapeutic intervention in T cell-mediated diseases.
Keywords: arthritis, co-stimulation, DTH, HAVcr1, proliferation
* These authors contributed equally to this study.
Transmitting editor: P. Kincade
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