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Mitochondrial Cyclophilin-D Regulates T Cell-Mediated Disease Tolerance to Tuberculosis
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A4314 - Mitochondrial Cyclophilin-D Regulates T Cell-Mediated Disease Tolerance to Tuberculosis
Author Block: N. Khan1, F. Tzelepis1, J. Blagih2, J. Gillard1, L. Mendonca1, D. G. Roy2, E. H. Ma2, P. Joubert3, R. G. Jones2, M. Divangahi1; 1Department of Medicine, McGill University, Montreal, QC, Canada, 2Goodman Cancer Research Centre and Department of Physiology, McGill University, Montreal, QC, Canada, 3Department of Pathology,, Quebec Heart and Lung Institute, Quebec, QC, Canada.
M. tuberculosis (Mtb) is one of the most ancient human pathogens, yet how our host defense fights Mtb remains unclear. Although 1/3 of the world’s population is chronically infected with Mtb, only 5-10% develops 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. Here we identify mitochondrial cyclophilin D (CypD) as a critical checkpoint of T cell metabolism that controls the expansion of activated T cells. While loss of CypD function in T cells led to enhanced Mtb-antigen specific T cell responses, surprisingly, this increased T cell response had no effect on bacterial burden. Rather, mice containing CypD-deficient T cells exhibited significantly compromised disease tolerance and succumbed to Mtb infection. This study establishes a mechanistic link between T cell mediated immunity and host tolerance in TB.
Author Block: N. Khan1, F. Tzelepis1, J. Blagih2, J. Gillard1, L. Mendonca1, D. G. Roy2, E. H. Ma2, P. Joubert3, R. G. Jones2, M. Divangahi1; 1Department of Medicine, McGill University, Montreal, QC, Canada, 2Goodman Cancer Research Centre and Department of Physiology, McGill University, Montreal, QC, Canada, 3Department of Pathology,, Quebec Heart and Lung Institute, Quebec, QC, Canada.
M. tuberculosis (Mtb) is one of the most ancient human pathogens, yet how our host defense fights Mtb remains unclear. Although 1/3 of the world’s population is chronically infected with Mtb, only 5-10% develops 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. Here we identify mitochondrial cyclophilin D (CypD) as a critical checkpoint of T cell metabolism that controls the expansion of activated T cells. While loss of CypD function in T cells led to enhanced Mtb-antigen specific T cell responses, surprisingly, this increased T cell response had no effect on bacterial burden. Rather, mice containing CypD-deficient T cells exhibited significantly compromised disease tolerance and succumbed to Mtb infection. This study establishes a mechanistic link between T cell mediated immunity and host tolerance in TB.
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