P159 Innate-like CD56 ⁺ CD8 ⁺ T cells exhibit bystander function and metabolic sensitivity in chronic hepatitis B

<h3></h3> CD56⁺ CD8⁺ T cells straddle innate and adaptive immunity, distinguished by natural killer receptor (NKR) expression and the capacity for TCR-independent, bystander effector functions. These cells are implicated in liver inflammation and may represent a barrier to immune restoration in chronic hepatitis B (CHB). Given emerging evidence that metabolic dysfunction-associated steatotic liver disease (MASLD) co-existing with CHB (CHB-MASLD) is associated with delayed viral responses and persistent inflammation, understanding the behaviour of CD56⁺ CD8⁺ T cells may provide insights into immunometabolic dysregulation relevant to both CHB and CHB-MASLD. We investigated circulating CD8⁺ T cells in healthy controls (HC) and CHB patients (treatment-naïve and on antiviral therapy, AVT). Multi-parameter flow cytometry was used to assess activation status, NKR expression, response to free fatty acids (FFAs), and effector function. CD8⁺ T cells were also sorted for transcriptomic analysis. Activated (CD38⁺HLA-DR⁺) CD8⁺ T cells expressing CD56 were significantly expanded in CHB patients compared to HCs, with increased expression of NKRs (NKG2A, NKp30). These innate-like CD56⁺ CD8⁺ T cells were more prevalent in ‘immune active’ than ‘immune control’ disease. AVT-treated patients had reduced proportions of CD56⁺ CD8⁺ T cells, yet their NKR expression remained high, indicating persistent innate-like signatures. Transcriptomic profiling revealed upregulation of innate-associated genes (e.g., KLRK1, NCR3) in AVT-treated patients compared to untreated controls. Functionally, CD56⁺ CD8⁺ T cells showed comparable IFN-γ production following TCR-dependent (anti-CD3/CD28) and TCR-independent (IL-15) stimulation, but TNF-α production was significantly higher following IL-15 stimulation, confirming a differential functional and bystander activation profile. These cells were also more susceptible to suppression by FFAs, suggesting functional vulnerability in metabolically altered environments. Our findings show that CD56⁺ CD8⁺ T cells with innate-like features are expanded and functionally distinct in CHB, with persistent NKR expression despite AVT and heightened sensitivity to metabolic cues. The susceptibility of these cells to FFAs supports a potential mechanistic link between metabolic dysfunction and immune dysregulation in CHB-MASLD. The exploration of the immunometabolic contribution of CD56⁺ CD8⁺ T cells to therapeutic resistance and liver disease progression appears critical in CHB and CHB-MASLD .