Mucosal‐Associated Invariant T Cell Dysregulation Correlates With Conjugated Bilirubin Level in Chronic HBV Infection

Background and Aims Mucosal‐associated invariant T (MAIT) cells are nonconventional T cells restricted to major histocompatibility complex class I–related protein 1 (MR1). They are highly abundant in human liver and activated by T‐cell receptor (TCR)‐dependent and TCR‐independent mechanisms to exhibit rapid, innate‐like effector responses. However, the roles of MAIT cells in chronic HBV infection are still open for study. This study aims to test their antiviral potential and investigate their dynamic changes and regulating factors during chronic HBV infection. Approach and Results Blood samples from 257 chronic HBV‐infected patients were enrolled, and nontumor liver specimens were collected from 58 HBV‐infected HCC patients. Combining cell‐culture experiments and human data, we showed that MAIT cells had strong cytotoxicity against HBV‐transfected hepatocytes in an MR1‐dependent way. However, circulating and hepatic MAIT cells in HBV‐infected patients decreased significantly compared to controls. Correlation analysis suggested that MAIT cell frequency was associated with disease progression and inversely correlated with serum‐conjugated bilirubin level. In particular, conjugated bilirubin not only directly promoted MAIT cell activation and apoptosis, but also impaired TCR‐induced proliferation and expansion of MAIT cells, which could be partially rescued by IL‐2 in the absence of conjugated bilirubin. Despite that MAIT cells from patients with high conjugated bilirubin levels showed decreased cytokine‐producing capacity, the increased TCR‐dependent antiviral cytokine production suggested MAIT cells as an important guardian of chronic HBV with high conjugated bilirubin. Conclusions We reveal the MR1‐dependent, anti‐HBV potential of MAIT cells and identify conjugated bilirubin as a major factor dysregulating its frequency and function in chronic HBV‐infected patients, suggesting a therapeutic target for MAIT‐cell–based immunity against chronic HBV infection.