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Abstract: FR-OR06

Novel Immune Checkpoint Molecule TIGIT Is Upregulated on Kidney CD4 T Cells and Mediates AKI in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Noel, Sanjeev, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • 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
  • Rabb, Hamid, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

T cells play important roles in acute kidney injury (AKI) but the molecular mechanisms are largely unknown. Our unbiased RNAseq analysis initially demonstrated increased mRNA expression of novel immune checkpoint molecule T cell immunoreceptor with Ig and ITIM domains (TIGIT) on kidney CD4 T cells after AKI. Here, we validated TIGIT expression on kidney T cells at protein level and investigated its effect on kidney T cell activation, function and AKI outcome.

Methods

C57BL/6J wild type (WT) mice underwent bilateral ischemia reperfusion (IR). TIGIT expression and effect on kidney T cell activation and cytokine expression was studied at baseline and after IR injury by flow cytometry in WT mice. TIGIT knockout (TIGIT KO) mice were used to assess effects on AKI. Human kidney at baseline and post ischemia for nephrectomy had CD4 TIGIT measured by flow cytometry.

Results

TIGIT expression increased significantly (p<0.001) on CD4 T cells in post IR kidneys compared to controls (15.0±1.5% vs 3.8±0.2%). Furthermore, TIGIT+ CD4 T cells from WT kidneys showed significantly increased expression of activation markers, CD25 (10.9±1.7% vs 2.4±0.2%, p<0.001), CD69 (14.5±1.4% vs 8.8±1.0%, p<0.01) and CD44 (93.9±1.5% vs 74.5±1.7%, p<0.001) compared to TIGIT- CD4 T cells. Intracellular cytokine analysis showed significantly increased IFNγ (50.4±3.4% vs 20.3±3.3%, p<0.001) and TNFα (55.7±5.0% vs 35.4±4.9%, p<0.02) expression by TIGIT+ CD4 T cells compared to TIGIT- CD4 T cell after IR injury in WT mice. TIGIT KO mice had significantly reduced SCr at 24h (2.1±0.2 vs 2.6±0.1 mg/dL; p=0.03) and 72h (1.3±0.3 vs 2.7±0.4 mg/dL; p=0.02) post IR compared to WT mice. At baseline, TIGIT KO mouse kidneys had significantly (p=0.03) reduced CD4 T cells compared to WT kidneys (59.2±1.7% vs 54.0±0.5%). CD4 T cells from ischemic human kidney had increased TIGIT expression compared to non-ischemic kidney (236.5±127.9 vs 24.75±19.4; p=0.15).

Conclusion

These data show that TIGIT expression increases on kidney CD4 T cells after ischemia in mice and humans. This correlates with increased CD4 activation and proinflammatory phenotype. Importantly, absence of TIGIT in mice reduced kidney dysfunction after AKI. TIGIT is a promising novel therapeutic target for AKI therapy and could also mediate other immune mediated kidney diseases.