Compromised Metabolic Reprogramming Is an Early Indicator of CD8+ T Cell Dysfunction during Chronic Mycobacterium tuberculosis Infection

The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in lung CD8+ T cells. As Mtb infection progresses, m...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 29; no. 11; pp. 3564 - 3579.e5
Main Authors:	Russell, Shannon L., Lamprecht, Dirk A., Mandizvo, Tawanda, Jones, Terrence T., Naidoo, Vanessa, Addicott, Kelvin W., Moodley, Chivonne, Ngcobo, Bongani, Crossman, David K., Wells, Gordon, Steyn, Adrie J.C.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-12-2019 Cell Press Elsevier
Subjects:	Animals bioenergetics CD8+ T cell CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cells, Cultured chronic infection Cytokines - metabolism exhaustion Female Glycolysis host-directed therapy Hypoglycemic Agents - pharmacology immunometabolism Latent Tuberculosis - immunology Latent Tuberculosis - microbiology metabolic reprograming metformin Metformin - pharmacology Mice Mice, Inbred C57BL Mitochondria - metabolism mitochondrial dysfunction Mycobacterium bovis - pathogenicity Mycobacterium tuberculosis - pathogenicity tuberculosis bioenergetics immunometabolism chronic infection tuberculosis exhaustion metformin mitochondrial dysfunction host-directed therapy CD8+ T cell metabolic reprograming
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Summary:	The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in lung CD8+ T cells. As Mtb infection progresses, mitochondrial metabolism deteriorates in CD8+ T cells, resulting in an increased dependency on glycolysis that potentiates inflammatory cytokine production. Over time, these cells develop bioenergetic deficiencies that reflect metabolic “quiescence.” This bioenergetic signature coincides with increased mitochondrial dysfunction and inhibitory receptor expression and was not observed in BCG infection. Remarkably, the Mtb-triggered decline in T cell bioenergetics can be reinvigorated by metformin, giving rise to an Mtb-specific CD8+ T cell population with improved metabolism. These findings provide insights into Mtb pathogenesis whereby glycolytic reprogramming and compromised mitochondrial function contribute to the breakdown of CD8+ T cell immunity during chronic disease, highlighting opportunities to reinvigorate immunity with metabolically targeted pharmacologic agents. [Display omitted] •T cells from Mtb and BCG infections have unique metabolic and functional signatures•Mitochondrial metabolism deteriorates in effector T cells as Mtb infection persists•Metformin rejuvenates mitochondrial metabolism in T cells from Mtb-infected mice•The breakdown of Mtb immunity during chronic disease is linked to immunometabolism T cell dysfunction contributes to the development of many chronic infections and cancer. Russell et al. show that chronic Mtb infection leads to a progressive decline in the metabolic health of effector T cells that reside in lung lesions. This metabolic reprograming can be reversed by treatment with metformin.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact Present address: Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium Present address: Public Health Laboratory, British Columbia Center for Disease Control, Vancouver, BC V5Z 4R4, Canada Present address: Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2019.11.034