T cell metabolism drives immunity

Abstract

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.

Figure 1.

Metabolism drives the life cycle of T cells. T cells engage specific metabolic pathways during development that underpin their differentiation and function. Naive T cells mature and exit from the thymus primarily relying on OXPHOS for their metabolic needs, although they augment with glycolytic metabolism during times of proliferation that follow TCR gene rearrangements. In secondary lymphoid organs, TCR ligation, costimulation, and growth factor cytokine signals induce clonal expansion and metabolic reprogramming of an antigen-specific T cell. This conversion to an activated effector T cell is marked by the engagement of aerobic glycolysis and increased OXPHOS activity. Glycolytic metabolism differentiates CD4 Th1, Th2, and Th17 effector cells (and possibly Tfh cells) from T reg cells. Promoting FAO and catabolic metabolism enhances T reg and memory T cell development (blue arrow). Memory T cells are a quiescent population of cells that primarily use OXPHOS, but both OXPHOS and glycolysis increase rapidly after antigen rechallenge and facilitate their recall responses.

Figure 2.

Metabolic pathways that support T cells. ATP is the molecular currency of energy in the cell. It can be derived from glucose through two integrated pathways. The first of these, glycolysis (green), involves the enzymatic breakdown of glucose to pyruvate in the cytoplasm. The TCA cycle (orange) encompasses the second pathway, where pyruvate is converted to acetyl-CoA in the mitochondria and shuttled through several enzymatic reactions to generate reducing equivalents to fuel OXPHOS (brown). Other substrates can also be metabolized in the TCA cycle, such as glutamine via glutaminolysis (purple) or fatty acids via β-oxidation (FAO; gray). These connected biochemical pathways can also provide metabolic precursors for biosynthesis. Intermediates from glucose catabolism during glycolysis can shuttle through the pentose phosphate (dark blue) and serine biosynthesis pathways (red) to fuel nucleotide and amino acid production. Oxaloacetate from the TCA cycle can similarly be used to generate aspartate for use in nucleotide synthesis. Precursors for amino acid and nucleotide biosynthesis can be obtained from glutamine. Citrate from the TCA cycle can be exported from the mitochondria and converted to acetyl-CoA for FAS (light blue). ROS generated from the ETC during OXPHOS can also act as secondary signaling molecules.