Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

Abstract

Significance Statement T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials. Background T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. Methods TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans. Results RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice. Conclusions TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI.

TIGIT regulates CD4+ T cell immunity against polymicrobial sepsis

“…In essence, TIGIT expression was induced upon stimulated with anti-CD3 and anti-CD28 in vitro and reached a peak at 24 hour and then decreased over time ( 18 ). Previous studies also showed that TIGIT-expressing T cells possessed a functionally proinflammatory profile and memory phenotype in context of experimental acute kidney injury, donor-specific hyperresponsiveness (DSH) and systemic lupus erythematosus (SLE) ( 39 – 41 ). TIGIT + CD8 + T cells were suggested to maintain an intrinsic capacity to kill targets in HIV-infected individuals instead of exhibiting an exhausted function ( 42 ).…”

“…Although TIGIT deficiency or TIGIT blockade led to increased T cell proliferation, robust cytokine production and degranulation ( 39 , 43 , 44 ), murine models of different disease backgrounds showed various responses to the loss of TIGIT signaling pathway. Blocking TIGIT by antibody or genetic knockout enhanced NK cell activation and aggravated liver injury in a poly I:C/D-GalN-induced model of acute hepatitis ( 26 ).…”

Comprehensive analysis of cuproptosis-related genes in immune infiltration and development of a novel diagnostic model for acute kidney injury

“…T lymphocytes mediate pathogenic and reparative processes during AKI, while the exact mechanisms regulating kidney T cell functions remain elusive [ 37 ]. Gong et al.…”

The Importance of Immune Checkpoint Molecule TIGIT in AKI

“…In the current issue of JASN, Béland et al provide an intriguing new insight into this area by demonstrating that HLA-DQ, DR, and DP proteins follow distinctly different expression dynamics on endothelial cells under inflammatory conditions. 9 Using human endothelial colony forming cell (ECFC)-derived cell lines, the authors observed that there was lower surface expression and greater interindividual variability of expression of HLA-DQ compared with HLA-DR and HLA-DP proteins after stimulation with IFNg. In pursuing this further, they assessed the relationship between HLA-DQ genotype and protein expression across their panel of ECFC-derived lines.…”

“…In this issue of JASN , Noel et al describe how TIGIT may mediate kidney T-cell contributions to AKI, providing evidence which supports its potential as a therapeutic target in human AKI. 9 To investigate the role of TIGIT in AKI, mice were subjected to either ischemia-reperfusion (IR) injury or cisplatin injection and human samples were obtained from patients undergoing nephrectomy both before and after renal pedicle clamping. The authors observed increased TIGIT expression in kidney CD4, CD8, and double-negative (DN) T-cell populations after murine IR injury and the percentage of human CD8+ and DN T cells that were TIGIT+ increased after renal pedicle clamping in human samples.…”