Follicular cytotoxic T cells is dysfunctional in chronic hepatitis B patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Given the impact of nonalcoholic fatty liver disease (NAFLD) on T cell activation and proliferation functions, we aim to explore the heterogeneity of follicular cytotoxic T (Tfc) cells in chronic hepatitis B (CHB) patients with NAFLD.

METHODS

32 healthy controls (HCs), 36 treatment-naïve CHB patients, and 19 treatment-naïve CHB + NAFLD patients were recruited. We employed multicolor flow cytometry to assess the exhausted phenotype and functionality of Tfc cells. CD8+ T cells were subjected to single-cell RNA sequencing. Furthermore, we co-cultured peripheral blood mononuclear cells from CHB patients with HepG2.2.15 cells under different treatment to investigate the underlying mechanism.

RESULTS

We observed an increased expression of inhibitory receptors in Tfc cells compared to their counterparts in CHB patients. In CHB + NAFLD patients the memory identity and functional properties of Tfc cells were impaired. Enhanced lipid oxidation and oxidative stress were found in the Tfc of CHB + NAFLD patients. Tfc cells were predominantly present within the exhausted effector T cells in CHB + NAFLD patients, while in CHB patients, Tfc cells were mainly distributed within the precursors of exhausted T cells and central memory T cells. The effector memory phenotype of Tfc cells was diminished but could be partially restored after antioxidant treatment.

CONCLUSION

We present the phenotype of Tfc cells in CHB patients, with or without NAFLD. Our findings provide evidence that the long-term memory identity and functionality of Tfc cells are impaired in CHB + NAFLD patients. Enhancing the characteristics of effector memory cells in Tfc through maintaining the redox balance may offer innovative therapeutic strategies for CHB + NAFLD patients.