Metabolic Instruction of Immunity

Abstract

Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.

Keywords: aerobic glycolysis; barrier immunity; checkpoint blockade; immunometabolism; immunotherapy; metabolism; mitochondria; mitochondrial dynamics; mucosa; tumor microenvironment.

Figure 1. Metabolic tug-of-war within the tumor microenvironment

The balance of nutrients and oxygen within the tumor microenvironment controls immune cell function. Glucose and amino acid consumption by tumor cells can outpace that of infiltrating immune cells, specifically depriving them of nutrients to fuel their effector function. Poorly perfused tumor regions drive hypoxia response programs in tumor cells, macrophages, and T cells. Increased HIF-1α activity in response to hypoxia or other mechanisms promotes glycolysis and increases concentrations of suppressive metabolites and acidification of the local environment. As a by-product of glycolysis, lactate concentration increases, which is coordinately utilized by tumor cells to fuel their metabolism, promotes macrophage polarization, and directly suppresses T cell function. The ability of T cells to target tumors is further limited by their upregulation of co-inhibitory receptors and engagement with their ligands on neighboring tumor cells and macrophages. As T cells progressively enter a dysfunctional state, their mitochondrial mass and oxidative capacity declines ultimately leading to their failure to meet bioenergetic demands to sustain effector functions and control tumor cell growth.

Figure 2. Recent highlights in the restructuring of intracellular architecture and metabolism

Immune cell function is a product of their metabolic state. Growth factor signaling, actin rearrangement, and glucose metabolism are closely intertwined. Actin-bound aldolase can be freed from the cytoskeleton downstream of growth factor signaling to mediate glycolysis. Engagement of this pathway is central to the activation and downstream effector functions of DCs, M1 macrophages, and T cells. T cells can dynamically restructure their mitochondria through processes like mitochondrial fission and fusion to signal changes in metabolism and to promote their long-term survival in the transition to memory cells.

Figure 3. Model of metabolic relationships in the gastrointestinal tract

The gut serves as a direct interface with the outside world and the foods we consume. A single epithelial cell layer separates the contents of the intestinal lumen from the lamina propria where DCs, macrophages, ILCs, and T cells reside. Peyer’s patches are interspersed along the epithelium, which in addition to supporting sampling of luminal antigens by DCs and M cells, house germinal centers that maturate IgA-secreting B cells with Tfh cell help. B cells augment glycolysis upon activation and depend on pyruvate import via Mpc2 for longevity as long-lived plasma cells (LLPCs). Plasma cell hunger for glucose may restrict this nutrient from Tfh cells, however Tfh cells downregulate glycolysis in response to expression of their lineage defining transcription factor Bcl6. In addition, GCs contain areas of hypoxia that impinge on B cell function like class switch recombination (CSR). Commensal bacteria produce metabolites such as short chain fatty acids (SCFAs) from the fermentation of dietary fiber, which influence B cell metabolism and promote IgA secretion. The presence of SCFAs and vitamins support maintenance of barrier function by promoting the development and survival of Tregs and ILCs, respectively. Homeostatic signals secreted by gut resident immune cells (e.g. IL-10) may also modulate metabolism and therefore control their activation state.

Figure 4. Tying organismal metabolism to cellular metabolism and immunity

Throughout the course of life, organisms are exposed to a variety of factors that influence their systemic metabolism and the relationship between these and immune cell metabolism is only beginning to be explored. As research moves forward, it will be important to understand how these challenges integrate with immune response programs and whether our current paradigms and models regarding immunometabolism match up or must be modified accordingly under these circumstances.