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

Abstract

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. : 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. Keywords: immunometabolism, CD8+ T cell, exhaustion, tuberculosis, mitochondrial dysfunction, bioenergetics, metformin, host-directed therapy, chronic infection, metabolic reprograming