Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization.

Area of Science:

• Immunology
• Vaccinology
• T cell biology

Background:

• T cell responses are crucial for immunity and modulated by inhibitory receptors.
• Adenovirus serotype 5 (Ad5) vectors induce T cell responses but may lead to immune dysfunction.
• Alternative serotype adenovirus vectors show promise for more functional T cell induction.

Purpose of the Study:

• To comprehensively characterize inhibitory receptor expression and memory markers in T cells after Ad5 versus alternative serotype adenovirus vaccination.
• To investigate the long-term functional recovery of Ad5-induced CD8 T cells.
• To explore strategies for overcoming Ad5-induced immune exhaustion.

Main Methods:

• Flow cytometry was used to measure inhibitory receptors (e.g., PD-1, Tim-3) and memory markers on CD8 T cells.
• Comparative analysis of T cell phenotypes at early and late time points post-vaccination with Ad5 and alternative serotype vectors (e.g., Ad26).
• Assessment of T cell recall responses following heterologous boosting and evaluation of vector dose effects.

Main Results:

• Ad5-induced CD8 T cells showed higher Tim-3 expression and reduced central memory differentiation compared to alternative serotypes, persisting for over a year.
• Ad26-primed mice demonstrated superior recall of SIV Gag-specific CD8 T cell responses after boosting.
• Lower Ad5 doses resulted in more boostable responses with less PD-1 expression than high Ad5 doses.

Conclusions:

• Ad5 vectors induce a persistent state of T cell exhaustion characterized by increased inhibitory receptor expression and impaired memory formation.
• Alternative serotype adenovirus vectors promote more durable and functional T cell immunity.
• Vector dose optimization and modulation of inhibitory signals are potential strategies to mitigate Ad5-induced immune dysfunction.