Granzyme B regulates antiviral CD8+ T cell responses

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells utilize the perforin/granzyme pathway for cell killing.
• Regulatory T cells (Tregs) also express functional granzymes and perforin, capable of inducing target cell death.
• Perforin deficiency in mice leads to detrimental immune over-responses during viral infections, suggesting a regulatory role for this pathway.

Purpose of the Study:

• To investigate the role of granzyme B (GZMB) in immune regulation during viral infections.
• To characterize the immune response in wild-type, GZMB-deficient, and perforin-deficient mice infected with Sendai virus.

Main Methods:

• Comparative analysis of immune responses in wild-type, GZMB-deficient, and perforin-deficient mice infected with Sendai virus.
• Quantification of viral titers and Ag-specific CD8(+) T cell populations in lungs and lymph nodes.
• Assessment of Treg function, including GZMB expression and suppression of CD8(+) T cell proliferation in vitro.

Main Results:

• GZMB-deficient mice exhibited a significant increase in Ag-specific CD8(+) T cells post-viral infection, with intact viral clearance.
• Perforin-deficient mice showed a less pronounced increase in CD8(+) T cells but impaired viral clearance.
• Tregs from wild-type mice expressed high GZMB during infection, and Treg depletion mimicked the CD8(+) T cell expansion seen in GZMB-deficient mice.
• GZMB-deficient Tregs demonstrated impaired suppression of CD8(+) T cell proliferation in vitro.

Conclusions:

• Granyzme B plays a crucial role in regulating the expansion of Ag-specific CD8(+) T cells during viral infections.
• This regulatory function is mediated, at least in part, through the action of granyzme B within the regulatory T cell compartment.
• These findings suggest that granyzme B is a key mediator of immune homeostasis in response to viral challenges.