CD96 marks a phenotypically distinct checkpoint-associated HCV-specific CD8+ T-cell subset featuring...

Area of Science:

• Immunology
• Virology
• T-cell biology

Background:

• Hepatitis C virus (HCV) infection often leads to chronic disease.
• Persistent HCV antigen exposure causes CD8+ T-cell exhaustion, characterized by inhibitory receptor upregulation and impaired function.
• While PD1 and TIGIT are known, CD96's role in HCV T-cell exhaustion is less understood.

Purpose of the Study:

• To investigate the role of CD96 in CD8+ T-cell phenotypes across different stages of HCV infection.
• To characterize CD96 co-expression with other inhibitory receptors and transcription factors in virus-specific T cells.

Main Methods:

• Utilized HCV-specific MHC class I tetramers and high-dimensional flow cytometry.
• Analyzed 32 patients across acute, subacute, chronic, resolved, and sustained virological response stages.
• Assessed CD96 co-expression with PD1, TIGIT, and key transcription factors (TCF1, TOX, IRF4).

Main Results:

• CD96+ HCV-specific CD8+ T cells were significantly increased across all infection stages compared to bulk CD8+ T cells.
• These CD96+ cells showed enrichment for IRF4+, TOX+, and TCF1+, suggesting memory-associated traits.
• The CD96+ PD1+ TIGIT+ subset was notably higher in HCV-specific T cells.

Conclusions:

• CD96 marks a distinct subset of HCV-specific CD8+ T cells with memory-associated phenotypes, not terminal exhaustion.
• These findings highlight CD96's potential as a biomarker and its implications for understanding T-cell dynamics in chronic viral infections.
• Further research is needed to explore the functional and therapeutic significance of CD96+ T cells in combination immunotherapies.