*Purpose: T cells play both pathogenic and reparative roles in kidney ischemia reperfusion injury (IRI) but the molecular mechanisms regulating kidney T cell functions are largely unknown. We originally performed unbiased RNA-seq analysis of murine kidney CD4 T cells and found increased expression of a novel immune checkpoint molecule T cell immunoreceptor with Ig and ITIM domains (Tigit) mRNA during kidney IRI. We hypothesize that TIGIT protein expression increases in both mouse and human kidney T cells during IRI, and that modulation of TIGIT can reduce tissue damage after IRI.

*Methods: Kidney IRI was induced in C57BL/6J wild type (WT) mice by bilateral renal pedicle clamping for 30 minutes followed by reperfusion. Kidney T cells were studied at baseline and after IRI to assess TIGIT expression, activation markers and cytokine expression by flow cytometry. TIGIT knockout (TIGIT KO) mice were used to assess TIGIT effect on AKI. TIGIT expression was assessed in human kidney CD4 T cells, isolated from nephrectomies for renal cell carcinoma, at baseline and post ischemia by flow cytometry.

*Results: TIGIT expression increased significantly (p<0.001) on CD4 (15.0±1.5% vs 3.8±0.2%) T cells in post IRI kidneys compared to controls. Furthermore, TIGIT+ CD4 T cells from WT kidneys expressed significantly increased level of 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. Additionally, TIGIT+ CD4 T cells 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 compared to TIGIT- CD4 T cells after IRI in WT mice. TIGIT KO mouse kidneys had significantly (p=0.03) reduced CD4 T cells (59.2±1.7% vs 54.0±0.5%) compared to WT kidneys, at steady state. 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 IRI compared to WT mice. TIGIT expression increased on CD4 T cells from ischemic human kidney compared to non-ischemic kidney (236.5±127.9 vs 24.75±19.4; p=0.15).

*Conclusions: These data demonstrate that TIGIT expression increases on kidney CD4 T cells after IRI in mice and humans. Furthermore, TIGIT expression correlates with increased activation and proinflammatory phenotype on kidney CD4 T cells. Importantly, TIGIT deficient mice were protected from experimental kidney IRI. TIGIT is a promising novel therapeutic target to improve deceased donor quality and quantity, as well as other T cell mediated kidney diseases.

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