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

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Science Immunology  11 May 2018:
Vol. 3, Issue 23, eaar4135
DOI: 10.1126/sciimmunol.aar4135

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Mycobacteria and metabolism

Since the discovery of Mycobacterium tuberculosis (Mtb) over a century ago, great progress has been made in defining mechanisms of host resistance to tuberculosis (TB). By contrast, our understanding of how 90 to 95% of infected individuals live with chronic TB is extremely limited. Here, Tzelepis et al. examine the role of mitochondrial matrix protein cyclophilin D (CypD) in T cells using a mouse model of Mtb infection. CypD-deficient mice were more susceptible to Mtb infection in spite of enhanced Mtb-specific T cell responses, which has no impact on curbing bacterial loads but substantially increased lung immunopathology. Their findings indicate that CypD is a critical checkpoint of T cell metabolism for regulating disease tolerance in TB.


Mycobacterium tuberculosis (Mtb) is one of the most ancient human pathogens, yet the exact mechanism(s) of host defense against Mtb remains unclear. Although one-third of the world’s population is chronically infected with Mtb, only 5 to 10% develop active disease. This indicates that, in addition to resistance mechanisms that control bacterial burden, the host has also evolved strategies to tolerate the presence of Mtb to limit disease severity. We identify mitochondrial cyclophilin D (CypD) as a critical checkpoint of T cell metabolism that controls the expansion of activated T cells. Although loss of CypD function in T cells led to enhanced Mtb antigen–specific T cell responses, this increased T cell response had no impact on bacterial burden. Rather, mice containing CypD-deficient T cells exhibited substantially compromised disease tolerance and succumbed to Mtb infection. This study establishes a mechanistic link between T cell–mediated immunity and disease tolerance during Mtb infection.

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