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Sci Immunol. 2018 May 11;3(23). pii: eaar4135. doi: 10.1126/sciimmunol.aar4135.

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

Author information

1
Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada.
2
Goodman Cancer Research Centre and Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
3
Department of Pathology, Quebec Heart and Lung Institute, Laval University, 2725 Chemin Sainte-Foy, Quebec, Quebec G1V 4G5, Canada.
4
Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada. maziar.divangahi@mcgill.ca.

Abstract

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.

PMID:
29752301
DOI:
10.1126/sciimmunol.aar4135
[Indexed for MEDLINE]

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