Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function

Abstract

Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging their acquired effector function. Metabolic reprograming from the naïve-state is required throughout these phases of activation1. In CD4 T cells, T cell receptor (TCR) ligation, along with co-stimulatory and cytokine signals induce a glycolytic anabolic program required for biomass generation, rapid proliferation, and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodeling) and function are coordinately orchestrated by signal transduction and transcriptional remodeling; however, it remains unclear whether these processes are independently regulated by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support T helper 1 (Th1) cell differentiation and effector function, biochemically uncoupling these processes. We find that the TCA cycle is required for terminal Th1 cell effector function through succinate dehydrogenase (SDH; Complex II), yet the activity of SDH suppresses Th1 cell proliferation and histone acetylation. In contrast, we show that Complex I of the electron transport chain (ETC), the malate-aspartate shuttle, and citrate export from the mitochondria are required to maintain aspartate synthesis necessary for Th cell proliferation. Furthermore, we find that mitochondrial citrate export and malate-aspartate shuttle promote histone acetylation and specifically regulate the expression of a set of genes involved in T cell activation, proliferation, and metabolic programming. Combining genetic, pharmacological, and metabolomics approaches, we demonstrate that T helper cell differentiation and terminal effector function can be biochemically uncoupled. These findings support a model in which the malate-aspartate shuttle, citrate export, and Complex I supply the substrates needed for proliferation and epigenetic remodeling during early T cell activation, while Complex II consumes the substrates of these pathways, antagonizing differentiation and enforcing terminal effector function. Our data suggest that transcriptional programming works in concert with a parallel biochemical network to enforce cell state.

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

“…Together, these data provide evidence that the regulation of pro-versus anti-inflammatory cytokine expression is regulated in a FAO-dependent manner in T regs . This adds to previous reports showing specific electron transport chain complexes differentially regulate proliferation and cytokine expression in Th1 T eff cells and provides evidence these two processes can be uncoupled metabolically ( 94 ).…”

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

“…Energy insufficiency in IECs enhanced susceptible to T-cell mediated cytotoxicity was observed in vivo with both chemical inhibition and IEC specific genetic ablation of SDHA studies. Thus succinate accumulation in IECs caused by SDHA reduction, i.e defect in mitochondrial complex II, is distinct from the mitochondrial defects observed in other contexts such as ischemia reperfusion model, LPS activated macrophages or in other mitochondrial complex deficiencies 21 22 32 . However, decreased NADH production by insufficient TCA cycle, a substrate for complex I reaction the starting point of ETC, could also secondarily contribute to further slowing down of the mitochondrial respiration and metabolic shutdown in the IECs caused by pathogenic T cells.…”

Human CD8+T-cells Require Glycolysis to Elicit Effector Function

“…The results here show that human naïve CD8 + T-cells require both mitochondria and glycolytic energy production for successful activation and resulting clonal expansion. Previous studies demonstrated that T-cell expansion can be improved by certain metabolites being present upon antigen stimulation, and that memory T-cells have a more catabolic metabolic profile compared to that of effector cells which exhibit more anabolic metabolic profiles 5,11 . When we ablated mitochondrial activity in vitro , naïve CD8 + T-cells were unable to become activated or expand, resulting in T-cell death.…”

“…It has also been shown T reg cells require mitochondrial complex III to maintain their regulatory gene expression and suppressive function 4 . Furthermore, the tricarboxylic acid cycle (TCA) is required for terminal effector function of T H 1 cells through succinate dehydrogenase (complex II), but the latter activity suppresses proliferation of activated mouse T H 1 CD4 + T-cells 5 .…”