Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins.
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 G(0)/G(1) 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 T(h)1-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.
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Mehdi
M
Mesri
Glennda
G
Smithson
Ashwini
A
Ghatpande
Andrei
A
Chapoval
Suresh
S
Shenoy
Ferenc
F
Boldog
Craig
C
Hackett
Carol E
CE
Pena
Catherine
C
Burgess
Alison
A
Bendele
Richard A
RA
Shimkets
Gary C
GC
Starling
D000818:Animals; D001168:Arthritis / Q000276:immunology / Q000517:prevention & control; D016466:CHO Cells; D002453:Cell Cycle; D006224:Cricetinae; D003412:Cricetulus; D003877:Dermatitis, Contact / Q000517:prevention & control; D016193:G1 Phase; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016192:Resting Phase, Cell Cycle; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015375:Receptors, Interleukin-2; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C500399:TIM-4 protein, mouse; C512411:TIMD4 protein, human