International Immunology Advance Access published online on February 15, 2006
International Immunology, doi:10.1093/intimm/dxh388
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1 CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA; Present address: Celera Genomics, 45 West Gude Drive, Rockville, MD 20850, USA
* To whom correspondence should be addressed. 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. *These authors contributed equally to this study.
Received September 14, 2005
Accepted December 22, 2005
Article
Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins
Mehdi Mesri 1 *,
Glennda Smithson 2 * *,
Ashwini Ghatpande 3,
Andrei Chapoval 3,
Suresh Shenoy 3,
Ferenc Boldog 3,
Craig Hackett 3,
Carol E. Pena 3,
Catherine Burgess 3,
Alison Bendele 4,
Richard A. Shimkets 3,
and
Gary C. Starling 5
2 CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA; Present address: 675 North Field Drive, Lake Forest, IL 60045, USA
3 CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA
4 Bolder BioPATH Inc., Boulder, CO, USA
5 CuraGen Corporation, 322 East Main Street, Branford, CT 06405, USA; Present address: PDL Bio Pharma, 34801 Campus Drive, Fremont, CA 94555, USA
Glennda Smithson, E-mail: info{at}curagen.com
Abstract
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