Mitochondrial metabolism is essential for invariant natural killer T cell development and function

Area of Science:

• Immunology
• Cellular Metabolism
• Mitochondrial Biology

Background:

• T cell function relies on signaling and mitochondrial metabolism.
• Invariant natural killer T (iNKT) cells are innate-like T cells in a preactivated state.
• The genetic and in vivo dependence of iNKT cells on mitochondrial metabolism is undefined.

Purpose of the Study:

• To genetically define the role of mitochondrial metabolism in iNKT cell development and function in vivo.
• To investigate the impact of mitochondrial complex III dysfunction on iNKT cell populations.

Main Methods:

• Generated mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP), an essential subunit of mitochondrial complex III.
• Analyzed iNKT cell development, apoptosis, proliferation, and activation markers in T-Uqcrfs1 knockout mice.
• Assessed T cell receptor (TCR) signaling, interleukin-15 stimulation responses, and cytokine production in iNKT cells.

Main Results:

• T cell-specific RISP ablation dramatically reduced iNKT cells but spared conventional T cell development.
• Impaired iNKT cell development resulted from a cell-autonomous defect, blocking early differentiation.
• Residual iNKT cells showed increased apoptosis, retained proliferation, but had reduced TCR signaling, activation markers, and cytokine production.

Conclusions:

• Mitochondrial metabolism, specifically via RISP, is crucial for iNKT cell development and differentiation.
• iNKT cell activation and function, including cytokine production, are dependent on mitochondrial complex III activity.
• Mitochondrial metabolism plays a vital role in iNKT cell biology beyond basic bioenergetic support.