Innate-Like Cd56+ Cd8+ T Cells Exhibit Bystander Function and Metabolic Sensitivity
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Authors
LungYi Mak L.
Xiong S.
Deschler S.
Pade C.
Fernandes C.
Miao T.
Lei Y.
HernandezMir G.
Riddell A.
Koffas A.
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2025
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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-naive 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-gamma production following TCR-dependent (anti-CD3/CD28) and TCR-independent (IL-15) stimulation, but TNF-alpha 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 innatelike 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 .
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Gut