Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Rachelle G. Veenstra, Patricia A. Taylor, Qing Zhou, Angela Panoskaltsis-Mortari, Mitsuomi Hirashima, Ryan Flynn, Derek Liu, Ana C. Anderson, Terry B. Strom, Vijay K. Kuchroo, Bruce R. Blazar

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)682-690
Number of pages9
JournalBlood
Volume120
Issue number3
DOIs
StatePublished - Jul 19 2012

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