Skewed ratios between CD3+ T cells and monocytes are associated with poor prognosis in patients with HBV-related acute-on-chronic liver failure

Tempering of the innate immune response by T lymphocytes has been demonstrated to play a critical role in protecting animals from inflammation-induced death; however, its role in humans remains unknown. Patients with HBV-related acute-on-chronic liver failure (ACLF) share a striking similarity to the inflammatory response in septic shock where a hyperactive innate response is observed. The present study attempted to characterize the features of CD3+ T cells and monocytes and evaluate their clinical implications in 55 patients with HBV-related ACLF, 30 patients with chronic hepatitis B (CHB) and 30 healthy controls (HC). We found that the ratio between circulating CD3+ T cells and monocytes (T/M) was decreased in ACLF patients, due to decreased CD3 counts and increased monocyte counts compared with CHB and HC subjects. We also found that the T/M ratios were decreased from the early to the intermediate stage and reached the lowest value at the late stage in ACLF patients. Analyses with clinical parameters revealed that T/M ratios were negatively correlated with the Model for End-Stage Liver Disease Score and direct bilirubin, and positively correlated with prothrombin activity. Moreover, increased T/M ratios were observed in patients with good prognosis, but not in patients with a poor outcome; and ACLF patients who received liver transplantation exhibited an increased T/M ratio. Importantly, we found that programmed death-1 receptor (PD-1) was drastically upregulated on both CD4+ T and CD8+ T cells in ACLF, which at least in part contributed to the T-cell loss in these patients. Mechanically, the in vitro co-culture assay revealed that both CD4+ T and CD8+ T cells, as well as regulatory T cells, could inhibit TNF-α secretion by monocytes. In addition, the TNF-α levels in ACLF serum were negatively correlated with T/M ratios. In conclusion, our study identified the novel potential role of T/M ratio in predicting disease progression and provided novel evidences for further studies of the immunopathogenesis in ACLF.

Research highlights
► The ratios between CD3+ T cells and monocytes (T/M) were decreased in ACLF.
► T/M ratios correlated with disease progression in ACLF.
► Upregulated expressions of PD-1 contributed to T-cell loss in ACLF.
► T lymphocytes, including CD3+ T, CD4+ T, CD8+ T cells, as well as Treg, could constrain TNF-α secretion by monocytes.
► TNF-α levels in ACLF serum were negatively correlated with T/M ratios.