Mitochondrial cyclophilin D regulates T cell metabolic responses and disease tolerance to tuberculosis

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Mycobacterium tuberculosis (Mtb) infection affects one-third of the global population, with only a fraction developing active disease.
• Host defense against Mtb involves both resistance (controlling bacterial load) and tolerance (limiting disease severity).
• Mechanisms underlying Mtb tolerance remain largely undefined.

Purpose of the Study:

• To identify host factors regulating T cell responses and disease tolerance during Mtb infection.
• To investigate the role of mitochondrial cyclophilin D (CypD) in T cell metabolism and Mtb pathogenesis.

Main Methods:

• Utilized a mouse model of Mtb infection.
• Generated T cells with CypD deficiency.
• Assessed T cell expansion, bacterial burden, and host survival.

Main Results:

• Loss of CypD in T cells enhanced Mtb antigen-specific T cell responses but did not reduce bacterial burden.
• Mice with CypD-deficient T cells showed significantly impaired disease tolerance.
• CypD-deficient T cell recipients succumbed more rapidly to Mtb infection.

Conclusions:

• Mitochondrial CypD is a critical regulator of T cell metabolism and expansion during Mtb infection.
• CypD in T cells is essential for host disease tolerance, independent of bacterial control.
• This study links T cell-mediated immunity to disease tolerance in Mtb pathogenesis.