Abstract: FR-PO098
Ischemia-Reperfusion Injury Affects Co-Signaling Molecules TIGIT/CD226 in Kidney T Cells
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Noel, Sanjeev, Johns Hopkins University, Baltimore, Maryland, United States
- Lee, Sul A, Johns Hopkins University, Baltimore, Maryland, United States
- Kurzhagen, Johanna T., Johns Hopkins University , Baltimore, Maryland, United States
- Sadasivam, Mohanraj, Johns Hopkins University, Baltimore, Maryland, United States
- Gharaie fathabad, Somayeh, Johns Hopkins University , Baltimore, Maryland, United States
- Hamad, Abdel, Johns Hopkins University , Baltimore, Maryland, United States
- Pierorazio, Phillip M., Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, United States
- Rabb, Hamid, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background
T-cells play important roles in AKI pathogenesis and repair processes, but detailed mechanisms are not known. Unbiased cell specific RNAseq is a powerful tool to discover new therapeutic targets, and led to the discovery of AKI stimulated kidney CD4 cell co-inhibitory molecule, T-cell immunoreceptor with Ig and ITIM domain (TIGIT) and its co-stimulatory counterpart CD226
Methods
8-week-old male C57BL6/J wild type (WT) mice underwent bilateral IR surgeries to induce AKI. CD4 T-cells from post ischemic and control kidney were flow sorted 24 hours after inducing AKI and RNA sequencing (RNA-seq) performed. Flow cytometric analysis was performed to validate RNA-seq findings in T-cells from post ischemic mouse kidney, and “normal” portion of pre and post-clamp human kidney samples of renal cell carcinoma nephrectomies
Results
RNA-seq analysis showed significant increase in TIGIT expression (63.0±12.6 vs 21.8±2.6; p≤0.03) in CD4 T-cells from post IR mouse kidneys compared to control. Alternatively, CD226 mRNA was significantly reduced (13.0±1.8 vs 78.4±4.0; p≤0.0001) in post IR kidney CD4 T-cells. Flow cytometric analysis showed significant TIGIT protein expression in CD4 (11.7±5.0 vs 2.3±1.6; p≤0.008) and CD8 (13.0±6.7 vs 4.3±0.7; p≤0.04) T-cells from post IR kidneys compared to control. CD226 protein expression was not different in CD4 and CD8 T-cell isolated from post IR and control kidneys, however, double negative T-cells (CD3+CD4-CD8-; DN) showed significantly reduced (17.1±6.8 vs 56.3±10.2; p≤0.0002) expression in post IR kidneys. Human kidney assessment showed significant increase in absolute number of TIGIT positive CD8 (74.9±22.7 vs 14.4±5.1; p≤0.04) and DN T-cells (18.1±4.9 vs 1.3±0.9; p≤0.01) as well as CD226 positive DN T-cells (23.8±6.2 vs 2.4±1.4; p≤0.01) in post-clamp “normal” human kidney compared to pre-clamp kidney tissue
Conclusion
These data demonstrate that ischemia reperfusion leads to marked changes in TIGIT and CD226 in mouse and human kidney T-cells. Given the effectiveness as well as renal side effects of traditional anti CTLA4 and anti PD1 therapies, TIGIT/CD226 may be a novel target for developing next generation check point inhibitor therapies for AKI and other kidney diseases
Funding
- NIDDK Support