Metabolic reprogramming and apoptosis sensitivity: Defining the contours of a T cell response

Abstract

An effective adaptive immune response hinges on the rapid clonal expansion of T cells in response to antigen. The sensitivity of these T cells to programmed cell death (i.e. apoptosis) is carefully calibrated at various stages to ensure a robust yet measured reaction that resolves without inflicting unintended damage to host tissues. To meet bioenergetic demands associated with vigorous proliferation, acquisition of effector functions, and memory formation, T cells also undergo dynamic changes in their metabolism at every stage of this response. In this review, we focus on relatively recent studies that illuminate intimate links between metabolic programs and apoptosis sensitivity in T cells. We then examine how these connections ultimately influence T cell survival and function within the metabolically taxing environs of the tumor microenvironment.

Keywords: Apoptosis; CWID; Cytokine withdrawal-induced cell death; Immunometabolism; Restimulation-induced cell death; T cells.

Figure 1. Sensitivity to critical apoptosis pathways correlates with metabolic reprogramming over the course of the T cell response

Naïve T cells exist in a metabolically quiescent state until antigen (Ag stimulation), which triggers increased Glut1-mediated glucose uptake and an abrupt increase in aerobic glycolysis (as well as OXPHOS). Enhanced glycolysis sensitizes effector T cells to RICD by enabling TCR-induced FASL induction upon Ag re-encounter. As Ag is cleared, most effector T cells are culled through CWID. Those T cells that persist into the memory pool likely escape both RICD and CWID by inducing protective autophagy and turning off glycolysis in favor of FAO-direct OXPHOS. This metabolic switch returns memory T cells to a more quiescent state, “primed” for rapid recall responses via increased spare respiratory capacity.

Figure 2. Exhausted TIL (T_EX) escape apoptosis via altered metabolism

Highly glycolytic T cells that infiltrate a solid tumor may be susceptible to RICD immediately upon repeated Ag encounter. However, the upregulation of co-inhibitory receptors like PD-1 attenuate TCR signal strength and promote FAO over glycolysis. This metabolic switch likely helps exhausted T_EX escape RICD despite chronic Ag exposure, and survive despite fierce completion for glucose, amino acids, and other nutrients inside the harsh tumor microenvironment. Eventually, severely exhausted T cells exhibit profound metabolic stress and likely become susceptible to CWID/ACAD in response to prolonged nutrient and cytokine deprivation.