De Novo Fatty Acid Synthesis During Mycobacterial Infection Is a Prerequisite for the Function of Highly Proliferative T Cells, But Not for Dendritic Cells or Macrophages

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, is able to efficiently manipulate the host immune system establishing chronic infection, yet the underlying mechanisms of immune evasion are not fully understood. Evidence suggests that this pathogen interferes with host cell lipid metabolism to ensure its persistence. Fatty acid metabolism is regulated by acetyl-CoA carboxylase (ACC) 1 and 2; both isoforms catalyze the conversion of acetyl-CoA into malonyl-CoA, but have distinct roles. ACC1 is located in the cytosol, where it regulates de novo fatty acid synthesis (FAS), while ACC2 is associated with the outer mitochondrial membrane, regulating fatty acid oxidation (FAO). In macrophages, mycobacteria induce metabolic changes that lead to the cytosolic accumulation of lipids. This reprogramming impairs macrophage activation and contributes to chronic infection. In dendritic cells (DCs), FAS has been suggested to underlie optimal cytokine production and antigen presentation, but little is known about the metabolic changes occurring in DCs upon mycobacterial infection and how they affect the outcome of the immune response. We therefore determined the role of fatty acid metabolism in myeloid cells and T cells during Mycobacterium bovis BCG or Mtb infection, using novel genetic mouse models that allow cell-specific deletion of ACC1 and ACC2 in DCs, macrophages, or T cells. Our results demonstrate that de novo FAS is induced in DCs and macrophages upon M. bovis BCG infection. However, ACC1 expression in DCs and macrophages is not required to control mycobacteria. Similarly, absence of ACC2 did not influence the ability of DCs and macrophages to cope with infection. Furthermore, deletion of ACC1 in DCs or macrophages had no effect on systemic pro-inflammatory cytokine production or T cell priming, suggesting that FAS is dispensable for an intact innate response against mycobacteria. In contrast, mice with a deletion of ACC1 specifically in T cells fail to generate efficient T helper 1 responses and succumb early to Mtb infection. In summary, our results reveal ACC1-dependent FAS as a crucial mechanism in T cells, but not DCs or macrophages, to fight against mycobacterial infection.

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

“…SREBP in T eff cells induces the expression of the enzymes acetyl-CoA carboxylase (ACC), fatty acid synthetase (FASN) and the hydroxy-methyl-glutaryl-CoA reductase (HMGCR), which are rate limiting in the synthesis of FAs and cholesterol, respectively (61). Recent studies have highlighted the importance of FAS in T cell activation and have proposed that inhibiting this pathway could potentially be used to modulate the differentiation of T eff cells (61–65). …”

“…In activated T cells, the endogenous synthesis of LCFAs and cholesterol relies heavily on acetyl-CoA obtained in the mitochondria after glycolysis which is exported to the cytoplasm and used to initiate lipid synthesis through a brief conjugation to mitochondrial oxaloacetate to form citrate (Figure 1). Endogenous FAS is necessary to sustain the expansion of activated T cells, as demonstrated by the impaired proliferation and effector response observed after genetic deletion of the SREBP cleavage-activating protein (SCAP) (61) or ACC1 (62, 63, 65, 68). This connection between the glycolytic and lipogenic pathways provides another reason why activated T cells and other cells that vigorously proliferate, such as tumour cells, depend to such degree on an upregulation of the glycolytic pathway, not only to produce ATP, but also to sustain anabolic reactions.…”

“…Accordingly, complete deletion of ACC2 in mice increases basal oxidation of LCFAs in muscle and reduces accumulation of fat (98, 99, 125), which can be attributed to increased CPT1 activity and transport of LCFAs into the mitochondria for oxidation. It is however not clear if T cells also employ this mechanism to regulate their rates of LC-FAO, given that ACC2 deletion in these cells has only very modest effects on FAO while not influencing their differentiation, effector function or memory development (25, 62, 65, 126). Instead, transcriptional regulation of Cpt1a expression could be more relevant in T cells.…”

“…given that ACC2 deletion in these cells has only very modest effects on FAO while not influencing their differentiation, effector function or memory development. 25,62,65,126 Instead, transcriptional regulation of Cpt1a expression could be more relevant in T cells. Indeed, it has been reported that PI3K-Akt-mTORC2 signaling initiated by growth factor or TCR/CD28 stimulation induces a downregulation of Cpt1a expression, 25,46,127,128 which in activated T cells is accompanied by a reduction of LC-FAO.…”

Emerging Roles of Cellular Metabolism in Regulating Dendritic Cell Subsets and Function

“…A third independent study suggests that fatty acid synthesis is dispensable for the activation and function of DCs. Indeed, ACC1-deficient iCD103 DCs (a BMDC subset that resembles and functions like CD103 + cDCs) or GM-CSF-BMDCs have normal functional capacity and activation, as revealed by normal expression of CD86 and MHC II, secretion of IL-12/23p40 and TNFα, and T cell priming ability following a bacterial infection ( Stüve et al, 2018 ). Thus, ACC1-mediated de novo fatty acid synthesis is dispensable for the function of iCD103 cDCs and GM-CSF-BMDCs.…”