Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion

By Bertram Bengsch, Andy L. Johnson, M. Kurachi, P. Odorizzi, Kristen E. Pauken, John Attanasio, Erietta Stelekati, Laura M. McLane, Michael A. Paley, Greg M. Delgoffe and 1 more. Immunity, 2016

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Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8+ T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8+ T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and up-regulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism may enhance checkpoint blockade outcomes.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4fb96716dcb25c84c32ac8c53a62310bfcd2cc0f

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Citations in the corpus

Metabolic Instruction of Immunity (2017, positive): “PD-1 not only suppresses TCR, PI3K and mTOR signaling in T cells, but also dampens glycolysis and promotes fatty acid oxidation (FAO) – features that may enhance the accumulation of suppressive regulatory CD4 T (Treg) cells in tumors (Bengsch et al., 2016; Parry et al., 2005; Patsoukis et al., 2015)”
T Cell Dysfunction in Cancer (2018, background): “…shown that PD-1 contributes to these early glycolytic and mitochondrial changes, as PD-1 deficient T cells do not undergo these metabolic changes in the murine LCMV model, and as the key metabolic regulator PPAR-gamma coactivator 1a (PGC-1a) is repressed by PD-1 triggering (Bengsch et al., 2016).”
Monocyte-Macrophages and T Cells in Atherosclerosis (2017, positive): “Interestingly, one mechanism of thede-activatingeffect ofPD-1onTcell activationcould involve PD-1-mediated suppression of glycolysis in the T cells themselves, as has been shown recently for CD8+ T cells (Bengsch et al., 2016).”
Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade (2017, neutral): “Two CD4 effector T cell subsets were identified in the TME, and both display an activated phenotype but differ in their expression of key markers including PD-1 and TBET (Figure 1G).”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “these metabolic defects, including PGC1α (106, 107) and Foxo1 (108) pathways.”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “During chronic viral infection, PGC1α overexpression promotes viral clearance by overcoming PD-1-mediated suppression of mitochondrial metabolism, facilitating the glycolytic reengagement needed for Te cell function (93).”