Metabolic regulation of innate and adaptive lymphocyte effector responses

At the time of intial priming, CD4+ T cells differentiate into various effector subsets, guided by specific antigen presenting cells and the cytokine mileu. Recent studies have defined that differentiation and subsequent effector functions are accompanied by a switch in the metabolic programming which occurs in a context-specific manner to meet the bioenergetic demands created during infection or inflammation 1. Deciphering the relative importance of distinct metabolic pathways employed by cells is essential for greater understanding of immune cell biology in order to design future therapeutics. However, delineating the metabolic dependencies of immune cells is complicated by the extensive interdependence between the primary bioenergetic pathways. In brief, cells derive energy, stored as ATP and NADH, from the oxidation of glucose through glycolysis, mitochondrial oxidative phosphorylation (OxPhos) and the electron transport chain (ETC), to generate CO2 and water. Glucose is lysed to pyruvate that is converted to acetyl CoA at the inner mitochondrial membrane. Acetyl CoA is then shuttled into the tricarboxylic acid (TCA) cycle by conversion to citrate. Alternatively, under conditions of limiting oxygen, acetyl CoA is converted to lactate with the regeneration of NAD+. Cells undergoing rapid proliferation such as tumor cells and activated T cells utilize this pathway despite oxygen availability (referred to as aerobic glycolysis or the Warburg effect), presumably to produce metabolites required for proliferation. Through the TCA cycle, acetyl CoA combines with oxaloacetate to form citrate and undergoes several conversions to reduce NAD+ to NADH for ATP generation via the ETC and yield metabolic intermediates for amino acid and fatty acid synthesis. Fatty acids (FA), like palmitate can serve as alternate source for acetyl CoA, through fatty acid oxidation (FAO), wherein FAs are catabolized to fatty acyl CoA and acetyl CoA. Furthermore, other catabolic pathways, such as glutaminolysis can feed into various stages of glycolysis and the TCA cycle thus providing an alternative fuel source. Also, metabolites from glycolysis are shuttled into the pentose phosphate pathway (PPP) for the synthesis of nucleotides 1,2. Intriguingly, T cells adapt their cellular metabolism to facilitate the bioenergetic needs of an appropriate immune response such as development or differentiation, cytokine production, and cell migration 2–4. This is best exemplified by the metabolic reprogramming that occur across subsets of CD4+ T helper (Th) cell populations in the context of infection or inflammation. Upon activation, naive CD4+ T cell differentiate into distinct fates as a result of the cytokine microenvironment and this process is essential to provide optimal immunity or drive chronic inflammatory diseases. T helper (Th)1 CD4+ T cells, represented as a T-bet+ IFN-γ-producing subset, control intracellular infections as well as tumor growth, or drive type-1 chronic inflammatory responses. GATA3+ Th2 CD4+ T cells produce IL-4, IL-5 and IL-13 to control helminth infections as well promote the wound healing process, or drive allergic inflammation. Th17 CD4+ T cells are RORγt+ IL-17 producers, found primarily in the intestinal mucosa and protect from pathogenic extracellular microbes, or drive chronic autoimmune inflammation. Finally, FoxP3+ regulatory T cells (Tregs) can differentiate in the thymus or the periphery limit excessive immune responses and autoimmunity 5. Distinct cell-intrinsic metabolic checkpoints have been identified in each subset and are discussed more in depth below. The innate lymphoid cell (ILC) family is defined by the lack classical lineage markers for CD4+ T cells, B cells, DCs, or macrophages, are enriched at barrier surfaces, and function primarily through the production of cytokines to modulate further immune responses, restore barrier integrity and maintain tissue homeostasis 6. ILCs can be considered an innate counterpart to the adaptive CD4+ T cell lineage, sharing similar transcriptional programs and cytokine effector profiles that allow them to be functionally classified into subsets analogous to helper CD4+ T cells. Group 1 ILCs (ILC1s) comprise NK cells and non-cytotoxic ILC1s that express T-bet and produce IFN-γ in response to infection 7. Group 2 ILCs (ILC2s) are GATA3+ cells capable of producing IL-5, IL-9, IL-13, and amphiregulin, serving critical roles in anti-parasitic immunity, allergic inflammation, and restoration of tissue integrity after damage 8. Group 3 ILCs (ILC3) express RORγt and produce IL-17 and IL-22 to combat intestinal infections, sustain intestinal barrier integrity, and maintain homeostasis with the commensal microbiota. ILC3 are further divided into T-bet+ ILC3s and CCR6+ lymphoid tissue inducer (LTi)-like ILC3s 6,9–11. In contrast to CD4+ T cells, how ILC function or migration is influenced by specific metabolic pathways remains poorly defined. While ILC and CD4+ T cell subsets share expression of canonical lineage transcription factors, ILCs are not activated by a T cell receptor or co-stimulatory signaling (a crucial signal for T cell metabolic programming) and therefore may be more dependent on cell-extrinsic cues from the tissue environment such as cytokines or diet- and microbial-derived metabolites. This review summarizes the current literature on the cell-intrinsic and context-dependent metabolic programs that control the functional potential of effector CD4+ T cells as well as the growing interest in interrogation of ILC metabolism. Further, we also speculate on the biological importance of the conserved vs unique features between ILC and CD4+ T cell metabolism, drawing focus to the potential clinical implications of these findings.