Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury.
T lymphocytes modulate early ischemia-reperfusion injury in the kidney; however, their role during repair is unknown. We studied the role of TCRbeta(+)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 TCRbeta(+)CD4(+) and TCRbeta(+)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-alpha generation by TCRbeta(+)CD4(+) T cells at 10 days. In separate mice, infusion of CD4(+)CD25(+) Tregs 1 day after initial injury reduced INF-gamma production by TCRbeta(+)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.
Gandolfo
Maria Teresa
MT
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jang
Hye Ryoun
HR
Bagnasco
Serena M
SM
Ko
Gang-Jee
GJ
Agreda
Patricia
P
Satpute
Shailesh R
SR
Crow
Michael T
MT
King
Landon S
LS
Rabb
Hamid
H
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D051858:Forkhead Transcription Factors; D051379:Mice; D012038:Regeneration / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse