Abstract
T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.
Highlights
The activation of T CD4 lymphocytes is triggered through the proper binding of the T-cell receptor (TCR) to specific antigens presented in the context of the major histocompatibility complex (MHC) on antigen presenting cells (APC), and of co-stimulatory molecules like CD28 with ligands such as CD80 and CD86, displayed on the APC membrane
A central actor in the lymphocyte metabolic activity is the AMPK complex, which is capable of sensing the intracellular AMP/ATP ratio, which represents the T cell energy pool availability, and of regulating the main metabolic pathways leading to the production of energy reserves (OXPHOS) or to the rapid generation of metabolites and structural proteins [47,48,49,50,51,52]
Afterwards, mTOR complex1 (mTORC1) is activated with the consequent inhibition of AMPK and the activation of glycolysis [55]
Summary
The activation of T CD4 lymphocytes is triggered through the proper binding of the T-cell receptor (TCR) to specific antigens presented in the context of the major histocompatibility complex (MHC) on antigen presenting cells (APC), and of co-stimulatory molecules like CD28 with ligands such as CD80 and CD86 (jointly denoted as CD80/86), displayed on the APC membrane. Binding of antigen to the TCR in the absence of CD28 ligation conduces to a state of anergy. In such a state, T cells are unable to produce interleukin 2 (IL-2) or proliferate on subsequent stimulations [14,15,16]
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