NADPH Oxidase 2-Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function

Area of Science:

• Immunology
• Cellular Biology
• Biochemistry

Background:

• Oxidants play a role in lymphocyte activation.
• NADPH oxidase 2 (NOX2) activity is essential for autoreactive CD8+ cytotoxic T lymphocyte (CTL) function.
• The precise molecular mechanisms by which NOX2 influences CD8+ T cell function are not fully understood.

Purpose of the Study:

• To investigate the role of NOX2 in the function of mouse and human CD8+ T cells.
• To elucidate the molecular mechanisms underlying NOX2's impact on CD8+ T cell effector functions.

Main Methods:

• Genetic ablation and chemical inhibition of NOX2 in CD8+ T cells.
• Analysis of T-bet expression and its target effector genes (IFN-γ, granzyme B).
• Assessment of target cell lysis.
• Investigation of redox signaling pathways involving superoxide, hydrogen peroxide, and the mTORC1 pathway.

Main Results:

• Genetic or chemical inhibition of NOX2 suppressed activation-induced T-bet expression and its target genes (IFN-γ, granzyme B) in CD8+ T cells.
• NOX2 inhibition prevented target cell lysis in both mouse and human CD8+ T cells.
• Superoxide generated by NOX2 must be converted to hydrogen peroxide for redox signaling.
• NOX2-generated oxidants deactivate a tumor suppressor complex, activating RheB and mTOR complex 1.

Conclusions:

• NOX2 plays a critical and nonredundant role in T cell receptor (TCR)-mediated CD8+ T cell effector functions.
• NOX2 regulates CD8+ T cell activation and cytotoxicity through redox signaling involving hydrogen peroxide and the mTORC1 pathway.