Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells.
T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3(+) T cells encounter high gal-9 levels, they are deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/gal-9 binding by infusion of a Tim-3-Ig fusion protein or Tim-3(-/-) donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was associated with decreased colonic inflammatory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3(-/-) donor T cells underwent increased activation-induced cell death because of increased IFN-γ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death.
University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, Minneapolis, MN 55455, USA.
Rachelle G
RG
Veenstra
Patricia A
PA
Taylor
Qing
Q
Zhou
Angela
A
Panoskaltsis-Mortari
Mitsuomi
M
Hirashima
Ryan
R
Flynn
Derek
D
Liu
Ana C
AC
Anderson
Terry B
TB
Strom
Vijay K
VK
Kuchroo
Bruce R
BR
Blazar
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D037161:Galectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D000072597:Hepatitis A Virus Cellular Receptor 2; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011991:Receptors, Virus; C508186:galectin 9, mouse; D007371:Interferon-gamma