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

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.

• Authors: Fanny Tzelepis, Julianna Blagih, Nargis Khan, Joshua Gillard, Laura Mendonca, Dominic G Roy, Eric H Ma, Philippe Joubert, Russell G Jones, Maziar Divangahi
• Journal: Science immunology (Sci Immunol) Vol. 3 Issue 23 (05 11 2018) ISSN: 2470-9468 [Electronic] United States
• PMID: 29752301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Cyclophilin D
• PPIF protein, mouse
• Cyclophilins

Topics

• Animals
• Cyclophilin D
• Cyclophilins (genetics, immunology)
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (immunology)
• Mycobacterium tuberculosis
• T-Lymphocytes (immunology)
• Tuberculosis, Pulmonary (immunology)