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.