title: Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gandolfo
authors.forename: Hye Ryoun
authors.initials: HR
authors.lastname: Jang
authors.forename: Serena M
authors.initials: SM
authors.lastname: Bagnasco
authors.forename: Gang-Jee
authors.initials: GJ
authors.lastname: Ko
authors.forename: Patricia
authors.initials: P
authors.lastname: Agreda
authors.forename: Shailesh R
authors.initials: SR
authors.lastname: Satpute
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
mesh_terms: 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
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse