MHC class I-restricted CD8+ T cells recognizing AAV capsid-derived peptides (AAV-specific CD8+ T cells)

MHC class I-restricted CD8+ T cells recognizing AAV capsid-derived peptides represent a critical immunological challenge in liver-directed gene therapy using Adeno-associated virus (AAV) vectors (Mingozzi & High, 2013, Nature Reviews Genetics). Following the administration of AAV vectors, the viral capsid proteins are internalized and processed by the hepatocyte's proteasomal machinery, leading to the presentation of capsid-derived peptides on the cell surface via MHC class I molecules (Finn et al., 2010, Molecular Therapy). CD8+ T cells that are specific to these AAV capsid antigens recognize these complexes and execute a cytotoxic attack on the transduced hepatocytes, which results in the destruction of the cells and the subsequent loss of the therapeutic transgene (Ertl, 2021, Frontiers in Immunology). This immune-mediated clearance is often clinically identified by a transient rise in liver transaminases, such as ALT and AST, which serve as surrogate biomarkers for the T-cell response (Manno et al., 2006, Nature Medicine). To mitigate this effect and ensure durable transgene expression, clinical protocols often incorporate prophylactic or reactive immunosuppressive therapies, such as Prednisone or Sirolimus, to inhibit the activation and expansion of these specific T-cell populations (Nathwani et al., 2011, NEJM). Successfully managing this T-cell response is essential for the safety and efficacy of gene therapies targeting conditions like hemophilia and various metabolic liver diseases.

Other names

AAV-specific cytotoxic T lymphocytesAAV-specific CTLsAnti-AAV capsid T-cell responseCapsid-specific CD8+ T cells

Systemic immunosuppression to inhibit the activation, expansion, and cytotoxic activity of AAV capsid-specific CD8+ T cells.