Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion

Abstract

Through the direct control of infection or by providing cytokine signals to other cellular players, T cells play a central role in the orchestration of the immune response. However, in many disease states, T cells are rendered dysfunctional, unable to carry out their effector functions. As T cell activation is bioenergetically demanding, some T cell dysfunction can have metabolic underpinnings. In this review, we will discuss how T cells are programmed to fuel their effector response, and how programmed or pathologic changes can disrupt their ability to generate the energy needed to proliferate and carry out their critical functions.

Keywords: Anergy; Exhaustion; Metabolism; T cells; Tolerance; mTOR.

Figure 1. T cell function and dysfunction are linked with metabolism

During normal T cell activation, cells receive TCR and CD28 stimulation, produce autocrine levels of IL-2, and respond to APC-produced differentiation cytokines, resulting in a switch to anabolic metabolism during their highly proliferative effector phase. When cells are rendered anergic, they receive only TCR stimulation with little accessory signaling, resulting in low autocrine levels of IL-2, a failure to commit to anabolic metabolism, and are transcriptionally programmed to downregulate metabolic machinery required to engage future effector responses. In situations of chronic activation, T cells also receive heightened inflammatory stimuli including interferons, TNF, and other cytokines, and begin to upregulate co-inhibitory molecules in an attempt to feedback on the immune response. These signals (and others) may restrain mTOR activation and anabolic metabolism, potentially creating a pathologic phenotype of metabolic insufficiency.