Postoperative cellular stress in the kidney is associated with an early systemic γδ T-cell immune cell response

Abstract

BackgroundBasic science data suggest that acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI) is an inflammatory process involving the adaptive immune response. Little is known about the T-cell contribution in the very early phase, so we investigated if tubular cellular stress expressed by elevated cell cycle biomarkers is associated with early changes in circulating T-cell subsets, applying a bedside-to-bench approach.MethodsOur observational pilot study included 20 consecutive patients undergoing endovascular aortic repair for aortic aneurysms affecting the renal arteries, thereby requiring brief kidney hypoperfusion and reperfusion. Clinical-grade flow cytometry-based immune monitoring of peripheral immune cell populations was conducted perioperatively and linked to tubular cell stress biomarkers ([TIMP-2]•[IGFBP7]) immediately after surgery. To confirm clinical results and prove T-cell infiltration in the kidney, we simulated tubular cellular injury in an established mouse model of mild renal IRI.ResultsA significant correlation between tubular cell injury and a peripheral decline of γδ T cells, but no other T-cell subpopulation, was discovered within the first 24 hours (r = 0.53; p = 0.022). Turning to a mouse model of kidney warm IRI, a similar decrease in circulating γδ T cells was found and concomitantly was associated with a 6.65-fold increase in γδ T cells (p = 0.002) in the kidney tissue without alterations in other T-cell subsets, consistent with our human data. In search of a mechanistic driver of IRI, we found that the damage-associated molecule high-mobility group box 1 protein HMGB1 was significantly elevated in the peripheral blood of clinical study subjects after tubular cell injury (p = 0.019). Correspondingly, HMGB1 RNA content was significantly elevated in the murine kidney.ConclusionsOur investigation supports a hypothesis that γδ T cells are important in the very early phase of human AKI and should be considered when designing clinical trials aimed at preventing kidney damage.Trial registrationClinicalTrials.gov, NCT01915446. Registered on 5 Aug 2013.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2094-x) contains supplementary material, which is available to authorized users.

Pattern of Tumor-Infiltrating Lymphocytes in Mixed Epithelial and Stromal Tumor of the Kidney: A Review of Five Cases

“…Furthermore, potent γδ T cell activation can be mediated by damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and high mobility group box 1 protein via pattern recognition receptors such as Toll-like receptors [23][24][25]. Correspondingly, dysregulated proliferation and malignant transformation of the epithelial and stromal components of MESTK could be sensed as DAMPs by γδ T cells, consistent with previous reports stating that oncogenic stress in renal tubular cells is sensed by the immune system via cell-cycle arrest and apoptosis induction [23][24][25][26].…”

Urinary [TIMP-2] × [IGFBP7] and serum procalcitonin to predict and assess the risk for short-term outcomes in septic and non-septic critically ill patients

“…Activated PBMCs and proinflammatory cytokines, such as tumour necrosis factor alpha and interleukin 1 are considered to play a role in PCT production and inflammation [24]. In a recent study by Gocze et al, a tubular stress detected by [TIMP-2] × [IGFBP7] positivity was associated with a systemic γδ T cell immune cell response [25].…”

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

“…Shortly after resection of gastric cancer, an increase in neutrophils accompanied by a decrease in the number of dendritic cells and T cells has been observed [237], which may suggest tumor-induced suppression of antigen presentation and impairment of effector functions. Postoperative cellular stress in people without a malignant tumor usually activates an immune response and mobilizes particular T cell subpopulations, which is associated with a local inflammatory infiltration of these cells [238]. On the other hand, surgical intervention normally triggers a shortterm immunosuppressive effect associated with the wound healing process, which may have an unfavorable prognostic value for patients with cancer due to an increase in the risk of metastases.…”