STING agonism turns human T cells into interferon-producing cells but impedes their functionality

Area of Science:

• Immunology
• Cellular Biology

Background:

• The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a key innate immune sensor for DNA.
• While STING is highly expressed in human T cells, its function and triggers in these cells are poorly understood.

Purpose of the Study:

• To investigate the functionality and impact of the cGAS-STING pathway in human primary T cells.
• To elucidate the downstream effects of cGAS-STING activation on T cell function and immunity.

Main Methods:

• Activation of the cGAS-STING pathway in human primary T cells using TCR-engaging signals.
• Assessment of T cell phenotypes, including cell death, proliferation, metabolism, and interferon production.
• Investigation of the roles of interferon regulatory factor 3 (IRF3) in mediating STING-dependent effects.

Main Results:

• The cGAS-STING pathway is functional in human T cells, inducing type I interferon production upon activation.
• STING activation leads to compromised T cell function, characterized by increased cell death, reduced proliferation, and impaired metabolism.
• Antiviral immunity and cell death are IRF3-dependent, while decreased proliferation occurs independently of IRF3.

Conclusions:

• Human T cells possess a functional cGAS-STING pathway that can contribute to antiviral defense.
• Activation of the cGAS-STING pathway detrimentally affects T cell function, irrespective of its antiviral role.
• Findings may guide the development of targeted immunotherapies involving the cGAS-STING pathway.