T lymphocytes modulate early ischemia-reperfusion injury in the kidney; however, their role during repair is unknown. We studied the role of TCRΒ CD4 CD25 Foxp3 regulatory T cells (Tregs), known to blunt immune responses, in repair after ischemia-reperfusion injury to the kidney. Using a murine model of ischemic acute kidney injury we found that there was a significant trafficking of Tregs into the kidneys after 3 and 10 days. Post-ischemic kidneys had increased numbers of TCRΒ CD4 and TCRΒ CD8 T cells with enhanced pro-inflammatory cytokine production. Treg depletion starting 1 day after ischemic injury using anti-CD25 antibodies increased renal tubular damage, reduced tubular proliferation at both time points, enhanced infiltrating T lymphocyte cytokine production at 3 days and TNF-α generation by TCRΒ CD4 T cells at 10 days. In separate mice, infusion of CD4 CD25 Tregs 1 day after initial injury reduced INF-γ production by TCRΒ CD4 T cells at 3 days, improved repair and reduced cytokine generation at 10 days. Treg manipulation had minimal effect on neutrophil and macrophage infiltration; Treg depletion worsened mortality and serum creatinine, while Treg infusion had a late beneficial effect on serum creatinine in bilateral ischemia. Our study demonstrates that Tregs infiltrate ischemic-reperfused kidneys during the healing process promoting repair, likely through modulation of pro-inflammatory cytokine production of other T cell subsets. Treg targeting could be a novel therapeutic approach to enhance recovery from ischemic acute kidney injury.
Bibliographical noteFunding Information:
We thank Priya Kesari for assistance with kidney bio-plex protein array and Lee Blosser and Ada Kam for assistance with flow cytometry analysis. We are grateful to Klaus B. Piontek for advice about Ki67 immunostaining, Franco D’Alessio for suggestions about PC61 mAb depletion strategy, and Luis Menezes and Yanfei Huang for helpful critical comments throughout the project. We submitted the abstract ‘Foxp3 + regulatory T cells participate in repair from kidney ischemia–reperfusion injury (IRI)’ to ASN Renal Week 2008. This study was supported by NIDDK R01 DK054770 to HR and NHLBI R01 HL089346 to LSK.
- Renal protection
ASJC Scopus subject areas