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Abstract: FR-PO173

Role of Double-Negative T Cells in Repair After Experimental Severe AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Lee, Kyungho, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Gharaie, Sepideh, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Kurzhagen, Johanna T., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Arend, Lois J., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Noel, Sanjeev, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Rabb, Hamid, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

T cells mediate organ injury and repair. A proportion of kidney αβ T cells are unconventional double-negative (DN) T cells (CD4- CD8-), which have anti-inflammatory properties previously demonstrated to protect from early injury in AKI. However, their role in repair from AKI has not been studied. We aimed to elucidate the role of DN T cells in AKI repair.

Methods

C57B6 mice underwent unilateral ischemia-reperfusion injury (IRI) surgery with 40 min ischemia. DN T cells, isolated from Faslgld mouse lymph nodes, were adoptively transferred AFTER IRI. Vehicle (neg. control) or Tregs (pos. control, Kidney Int 2009 PMID: 19625990) were also injected. GFR was measured by FITC-sinistrin-based method. Fibrosis was assessed with Masson trichrome staining. Profibrotic genes were measured with quantitative RT-PCR. T cells from postischemic kidneys were studied by flow cytometry.

Results

Percentages and the numbers of DN T cells markedly decreased in postischemic kidneys at 3 weeks from IRI compared to normal kidneys (18.7±1.1 vs 6.9±0.5% of αβ T cells, P<.001, 5.9±0.6×104 vs 0.9±0.3×104 cells/kidney, P<.001). DN T cell CD44 (95.0±0.4 vs 90.8±0.7%, P<.001) and CD69 (94.1±0.3 vs 85.8±1.1%, P<.001) were reduced, while DN T immune checkpoint TIGIT (0.6±0.2 vs 2.5±0.5%, P=.005) and NK1.1 (35.9±2.6 vs 52.4±3.5%, P=.004) were upregulated. Post-AKI transfer of DN T cells improved renal recovery, as did Treg transfer, with 3 week-GFR of 1176±27 μL/min/100g (vehicle, 1076±25, P=.001; Treg 1217±42, P=.399) and outer medullary fibrosis of 64.5±2.3% (vehicle, 82.0±1.9, P<.001; Treg 45.4±9.3%, P=.058). Tgfb1 was lower in the DN T cell transfer group (1.0±0.1 fold) than vehicle group (vehicle, 1.3±0.1, P=.012; Treg, 0.8±0.1, P=.226). Postischemic kidneys from DN T cell transferred mice had less effector memory CD4 T cells (94.7±0.2%) compared to those from vehicle group (vehicle, 96.9±0.3, P<.001; Treg 93.7±0.3%, P=.021). DN T cell transfer enhanced tubular proliferation, with higher Ki67 expression of CD45- E-cadherin+ cells (73.4±1.1; vehicle, 68.5±1.2, P=.011; Treg, 71.8±2.2%, P=.304).

Conclusion

Kidney DN T cells undergo quantitative and phenotypical changes long-term after severe ischemic kidney injury. Post-injury infusions of DN T cells, like T regs, can hasten repair and decrease fibrosis. A potential mechanism is by regulating kidney CD4 T cells.

Funding

  • NIDDK Support