Education-dependent activation of glycolysis promotes the cytolytic potency of licensed human natural killer cells

Publication date: Available online 7 August 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Jolie R. Schafer, Travis C. Salzillo, Nitin Chakravarti, Meisam Naeimi Kararoudi, Prashant Trikha, Jennifer A. Foltz, Ruoning Wang, Shulin Li, Dean A. Lee

Abstract

The mechanism by which natural killer (NK) cell education results in licensed NK cells with heightened effector function against missing-self targets is not known. We found that licensed human NK cells are higher in number in peripheral blood and proliferate more in vitro than unlicensed NK cells. Using high-throughput protein analysis, we found that unstimulated licensed NK cells have increased expression of the glycolytic enzyme PKM2, and after KIR crosslinking have increased phosphorylation of the metabolic modulators p38-α and AMPKα. Following cytokine expansion and activation, unlicensed NK cells solely depended on mitochondrial respiration for cytolytic function, whereas licensed NK cells demonstrated metabolic reprogramming toward glycolysis and mitochondrial-dependent glutaminolysis, leading to accumulation of glycolytic metabolites and depletion of glutamate. As such, blocking both glycolysis and mitochondrial-dependent respiration was required to suppress cytotoxicity of licensed NK cells. Collectively, our data support an arming model of education in which enhanced glycolysis in licensed NK cells supports proliferative and cytotoxic capacity.

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