CD4+ T cells promote renal fibrosis after acute kidney injury

Abstract

Acute kidney injury (AKI) is a syndrome defined by a sudden decrease in kidney function, primarily manifesting in impaired glomerular filtration. In high-income countries, AKI constitutes a major challenge for the health care system. Although kidney function impairment clinically resolves in most cases of AKI, emerging evidence indicates that AKI frequently leads to long-term structural damage within the kidney parenchyma, resulting in an increased risk for development of chronic kidney disease (CKD), a leading cause of global mortality. Despite recent research efforts, immunological mechanisms underlying AKI to CKD progression are still incompletely understood and effective therapeutic interventions to attenuate this progression are still lacking. To investigate the role of the immune system in progression of AKI to CKD, and to identify cell types involved in initiation of profibrotic processes responsible for long-term kidney failure, a mouse model of nephrotoxic AKI was established for this thesis. The cytotoxic drug cisplatin, a chemotherapeutic drug widely used in the clinic for cancer therapies, was employed to induce kidney injury, as it is known to cause damage to renal proximal tubular epithelial cells as a major off-target effect. Analysis of clinical markers showed that two low doses of cisplatin induced severe AKI while allowing long-term survival of mice. Excretory kidney function recovered by week 4, indicating clinical resolution of AKI. From week 10 onwards, histological fibrosis staining revealed progressive kidney fibrosis, a hallmark of CKD, in cisplatin-treated mice, despite apparent functional recovery from AKI. Notably, CD3+ immune cell infiltration, particularly by CD4+ T cells, into kidney tissue preceded the onset of kidney fibrosis by weeks, identifying a potential therapeutic window post-AKI. Gain- and loss-of-function experiments provided functional evidence that CD4+ T cells are critical drivers of fibrosis development after resolving AKI. Single-cell RNAseq analyses further revealed a stress response in cisplatin-treated tubular cells and a shift in the CD4+ T cell compartment from regulatory / Tr1-like cells to pro-inflammatory TNF+ and IFNγ+ tissue-resident memory T cells during AKI to CKD transition. In conclusion, this study provides evidence for a working model in which an AKI-induced population of CD4+ TRM cells contributes to a persistent inflammatory niche in the kidney tissue by producing pro-inflammatory and profibrotic cytokines. This might promote ongoing immune activation, tissue injury, and fibrotic remodelling. Through direct crosstalk with resident fibroblasts, TRM cells may drive the differentiation of fibroblasts into myofibroblasts, promoting maladaptive repair even after apparent recovery of injured PTECs. These findings suggest that targeting CD4+ TRM cells could represent a promising therapeutic strategy to prevent AKI to CKD progression.