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Abstract: FR-OR19

TIGIT Modulates Kidney T Cell Memory Phenotype and Metabolic Profile and Mediates Both Ischemic and Nephrotoxic AKI in Mice

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 05:42 PM - 05:51 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

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

T cells play pathogenic and reparative roles in acute kidney injury (AKI) but mechanisms regulating their functions are poorly understood. We found upregulated expression of the novel immune checkpoint molecule T cell immunoreceptor with Ig and ITIM domains (TIGIT) on kidney CD4 T cells after ischemia reperfusion (IR) using RNA-Seq. We explored TIGIT effect on kidney T cells, AKI outcomes and mechanisms.

Methods

TIGIT effect on murine kidney T cells was assessed at baseline and after ischemic AKI by flow cytometry and single cell RNA sequencing (scRNA-Seq). B6 wild type (WT) and TIGIT knockout (KO) mice were studied during ischemic and cisplatin-induced AKI. TIGIT expression was assessed in AKI patients using the Kidney Precision Medicine Project (KPMP) scRNA-Seq dataset.

Results

Ischemic AKI in WT mice led to an increase in kidney CD4+TIGIT+ effector memory (EM; 79.4±3.9 vs 65.4±5.4%, p=0.05) and central memory (CM; 10.0±2.3 vs 0.9±0.1%, p=0.001) cells compared to CD4+TIGIT- cells. CD4+TIGIT+ T cells had increased mean fluorescent intensity (MFI) of CD44 and reduced MFI of CD62L at baseline and after IR injury. TIGIT KO mice had significantly reduced serum creatinine (SCr) after IR (24h Scr, 1.1±0.2 vs 2.7±0.1 mg/dL; p≤0.001) and cisplatin (72h Scr, 0.8±0.1 vs 1.4±0.1 mg/dL; p=0.0002) injury compared to WT mice. TIGIT KO kidneys had significantly reduced necrotic tubules in outer medulla after IR (48.8±4.7% vs 73.0±1.5%; p=0.001) and cisplatin (11.5±3.0% vs 31.3±4.0%; p=0.008) injury than WT kidneys. scRNA-Seq analysis showed enrichment of inflammatory genes in Th1 and Th17 cells from WT kidney. Th1 and Th17 cells from TIGIT KO kidney had an enrichment of oxidative phosphorylation and mTORC1 signaling related genes. Human KPMP data demonstrated increased TIGIT expression in kidney T/NK cells of AKI patients compared to controls (p≤0.0001).

Conclusion

TIGIT is a direct pathophysiologic mediator of both experimental ischemic and nephrotoxic AKI. Kidney CD4 TIGIT expression correlated with effector and central memory phenotype, and distinct inflammatory/metabolic transcriptional profiles. TIGIT expression also increased in kidney T cells from AKI patients. TIGIT is a promising novel therapeutic target for AKI, and also relevant due to increasing use of TIGIT blockade to treat cancer.

Funding

  • NIDDK Support