Role of the T-cell receptor in kidney ischemia–reperfusion injury

Abstract

T cells have been demonstrated to modulate ischemia-reperfusion injury (IRI) in kidney, lung, liver and intestine. The underlying mechanisms for T-cell engagement in IRI are unknown. We hypothesized that the T-cell receptor (TCR) plays a role in renal IRI, and examined the effects of TCR alpha/beta (alphabeta) and gamma/delta (gammadelta) deficiency on ischemic acute renal failure (ARF). TCR-specific deficiency in specific mice was confirmed by fluorescence-activated cell sorting analysis using monoclonal antibodies (Abs). IRI was induced by bilateral clamping of kidney pedicles for 30 min, followed by reperfusion. Serum creatinine and kidney histopathology were used to assess the severity of experimental ARF. TCR alphabeta-deficient mice were significantly protected from kidney dysfunction compared to wild-type (WT) littermates after IRI (P<0.05). Histologic analysis demonstrated a significant reduction in renal tubular injury in both TCR alphabeta- and gammadelta-deficient mice compared to WT mice postischemia. TCR alphabeta-deficient mice had reduced tumor necrosis factor-alpha and interleukin-6 protein expression in kidney tissue compared to WT mice at 24 h postischemia using a microbead-based protein detection platform. Relative protection from kidney IRI did not correlate with neutrophil and macrophage infiltration of kidney tissue. Thus, the TCR plays a direct but modest pathophysiological role in kidney IRI. These data suggest that alloantigen-independent activation in IRI can lead to engagement of antigen-specific molecules on T cells. Furthermore, given that the TCR is already a target for diagnostics and therapeutic strategies in immune diseases, these approaches can now be harnessed for IRI.

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…We have previously reported that ␥␦ T cells mediate intestinal neutrophil recruitment in a peritoneal sepsis model (39). Similar to those studies (39) and others in a renal I/R model (13,36), we found no correlation between altered neutrophil recruitment and hepatic I/R injury in TCR-␦-deficient mice. Therefore, it appears that ␥␦ T cells mediate neutrophil recruitment into the site of inflammation in a manner that is independent of the degree of tissue damage.…”

“…Interestingly, previous findings regarding renal I/R in TCR-␦-deficient mice have demonstrated that TCR-␦-deficient mice show decreased serum creatinine levels, improved pathological findings, and better survival rate after 72 h of reperfusion compared with wild-type mice (36). We have previously shown that after hepatic I/R, signals for liver recovery/regeneration do not occur until after 24 h of reperfusion (3,22).…”

“…␥␦ T cells have been reported to regulate the inflammatory response induced by bacterial infection (8,39). Moreover, several reports have demonstrated that ␥␦ T cells mediate renal I/R injury, since TCR-␦-deficient mice show less renal injury during I/R compared with wild-type mice (13,36). To determine the effects of TCR-dependent ␥␦ T cell activation on hepatic I/R injury, TCR-␦-deficient mice and their wild-type controls were subjected to I/R.…”

“…In addition, we have demonstrated that neutrophil recruitment to the site of inflammation is mediated by ␥␦ T cells in the murine model of sepsis induced by cecal ligation and puncture (39). However, little is known about the role of ␥␦ T cells during hepatic I/R injury although several studies have shown that ␥␦ T cells mediate renal I/R injury (13,36).…”

Genomic Profiling of Kidney Ischemia-Reperfusion Reveals Expression of Specific Alloimmunity-Associated Genes: Linking “Immune” and “Nonimmune” Injury Events

“…Allograft injury pathways are represented by two major types of responses, antigen-dependent and antigen-independent. The antigen-dependent IRIresponse is characterized by upregulation of major histocompatibility complex (MHC) antigen expression (4,5) which is interconnected with antigen-independent pathways (6)(7)(8) represented by innate-immunity (9,10), complement (11,12) and pro-inflammatory cytokine/chemokine (13-15) driven responses. We therefore hypothesized that global gene expression profiling of immune-related genes during development of IRI could reveal key mechanisms how alloantigen-independent injury enhances alloreactivity.…”