TY - JOUR
T1 - Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells
AU - Veenstra, Rachelle G.
AU - Taylor, Patricia A.
AU - Zhou, Qing
AU - Panoskaltsis-Mortari, Angela
AU - Hirashima, Mitsuomi
AU - Flynn, Ryan
AU - Liu, Derek
AU - Anderson, Ana C.
AU - Strom, Terry B.
AU - Kuchroo, Vijay K.
AU - Blazar, Bruce R.
PY - 2012/7/19
Y1 - 2012/7/19
N2 - 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 donorTregs typically inhibitGVHD,undersome conditions, such Tregs actuallymaycontribute toGVHDby reducing activation-induced T-cell death.
AB - 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 donorTregs typically inhibitGVHD,undersome conditions, such Tregs actuallymaycontribute toGVHDby reducing activation-induced T-cell death.
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U2 - 10.1182/blood-2011-10-387977
DO - 10.1182/blood-2011-10-387977
M3 - Article
C2 - 22677125
AN - SCOPUS:84864129808
SN - 0006-4971
VL - 120
SP - 682
EP - 690
JO - Blood
JF - Blood
IS - 3
ER -