Regulatory T cells (Tregs) protect the kidney from inflammation, tissue damage and loss of function induced by ischemia-reperfusion (IR) in an IL-10 and PD-1 dependent manner, but the mechanisms of action for Tregs in IR are not completely understood. We hypothesized that Treg PD-1 is engaged by its ligand B7-H1, leading to increased IL-10 production by Tregs, which suppresses inflammation and protects from kidney IR. Similar to our previous observation that WT Tregs lose their ability to protect mice from kidney IR if treated with a PD-1 blocking antibody (ex vivo, prior to adoptive transfer), PD-1 KO Tregs did not offer any protection from kidney IR. In a model of mild renal IR that does not result in significant renal dysfunction in isotype control antibody-treated mice (plasma creatinine (PCr) level: 0.5±0.1, n=5 vs. sham PCr: 0.3±0.1, n=3) blockade of B7-H1 prior to IR causes a marked reduction in renal function (PCr: 1.3±0.3, n=6) accompanied by increased acute tubular necrosis and accumulation of neutrophils in the kidney. Stimulation of isolated WT Tregs with plate-bound anti-CD3, in the presence of IL-2, resulted in significant production of IL-10. In contrast to our hypothesis, addition of plate-bound B7-H1 Ig fusion protein dose-dependently inhibited IL-10 production by WT Tregs. Taken together these results suggest PD-1 and its ligand B7-H1 interact to protect from ischemic kidney injury, but argue against enhanced IL-10 production by Tregs as the mechanism.
- Copyright © 2013 by The American Association of Immunologists, Inc.