Abstract
SummaryThe 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.
Highlights
Our current understanding of what governs tuberculosis (TB) disease progression and control in humans is limited by the lack of existing knowledge about how protective immune responses are generated within TB lesions
To test our hypothesis that chronic Mycobacterium tuberculosis (Mtb) infection coincides with metabolic alterations in the CD8+ T cell population that impede downstream effector function and hinder disease resolution, we compared mice infected with pathogenic Mtb with mice infected with the non-pathogenic vaccine strain, M. bovis Bacillus CalmetteGuerin (BCG)
The magnitude of genes differentially expressed during Mtb infection relative to BCG when normalized to UI (1,747 versus 703 at D21 and 1,567 versus 821 at W12 for Mtb and BCG, respectively; Figure 1C), as well as the influence of time (D21 versus W12), suggests that different infection kinetics early on could play a role in promoting protective versus pathogenic T cell responses over time
Summary
Our current understanding of what governs tuberculosis (TB) disease progression and control in humans is limited by the lack of existing knowledge about how protective immune responses are generated within TB lesions. The central dogma suggests that within TB lesions, infected macrophages are activated by antigen-specific CD4+ T cells that secrete interferongamma (IFN-g), restricting the growth and dissemination of Mycobacterium tuberculosis (Mtb) (Nunes-Alves et al, 2014) This dogma has since been revised to recognize the importance of additional T cell subsets that elicit protective immune responses to Mtb. There is increasing evidence that CD8+ T cells are important for effective control of Mtb because they kill infected host cells directly and facilitate long-lived immunological memory (Chen et al, 2009; Flynn et al, 1992; Stenger et al, 1998; van Pinxteren et al, 2000). Failure to develop and sustain this essential antigenexperienced CD8+ T cell population during Mtb infection suggests that there may be a defect in key regulatory mechanisms that foster the differentiation of CD8+ effector T cells into longlived, multi-potent memory cells
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