Unlocking the immune puzzle: T Cell exhaustion in cirrhosis and implication for immunotherapy

Abstract

Cirrhosis, an advanced stage of liver disease, induces cirrhosis-associated immune dysfunction syndrome (CAIDS), characterized by both innate and adaptive immune dysfunction. Inflammation triggered by factors such as alcohol, viruses, toxins, and cholesterol induces metabolic reprogramming of both innate and adaptive immune cells. Our study specifically sought to investigate the compromised adaptive immune response in cirrhosis by focusing on assessing T-cell exhaustion and activation markers on helper and cytotoxic T cells. A prospective observational study involving 19 liver cirrhosis patients and 36 healthy controls was conducted. The hepatic decompensation degree was assessed using various parameters, including serum bilirubin, albumin, international normalized ratio, ascites, and hepatic encephalopathy. T cell activation (CD38, CD44, CD69, HLADR) and exhaustion markers (CTLA-4, PD-1, TIM-3, LAG-3) were assessed on helper and cytotoxic T cells by flow cytometry. Cirrhosis patients showed reduced T cells with no alteration in the CD4:CD8 T cell ratio. Among activation markers, HLADR showed increased expression on CD8+ T cells (p = 0.031). Regarding exhaustion markers, LAG-3 and TIM-3 exhibited increased expression in cirrhotic patients compared to controls in both CD4 and CD8 T cells (p = 0.004, p = 0.016, p = 0.001, p = 0.004, respectively). Neither cirrhotic nor healthy controls showed CTLA expression. PD-1 did not differ significantly between the two groups. Co-expression of PD-1/TIM-3 on CD8+ T cells was notably higher in cirrhotic patients (p < 0.002). The observation of impaired adaptive immunity with notable T-cell exhaustion and activation in cirrhosis underscores the potential relevance of immunotherapy.