Continuous Modeling of T CD4 Lymphocyte Activation and Function

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.

Depleted-MLH1 Expression Predicts Prognosis and Immunotherapeutic Efficacy in Uterine Corpus Endometrial Cancer: An In Silico Approach

“…Thereof, positive correlations were observed in MLH1 expression with immunoinhibitors IL10 and IL10RB, immunostimulators CD40 and CXCL12, and MHC genes HLA-DOA and HLA-DMB (Figure 7A-C). Moreover, CD4+ T cell activation was observed with MLH1 expression in UCEC (Figure 7D), which is consistent with the previous report [52]. These comprehensive results suggest that MLH1 expression may serve as a crucial mediator of immune-related biomolecules and lymphocytes within the tumor immune microenvironment [53].…”

Hepatic mRNA expression of innate and adaptive immune genes in beef steers with divergent residual body weight gain

“…CD80, primarily expressed on antigen-presenting cells like macrophages and dendritic cells, interacts with its receptor CD28 on T cells, providing costimulatory signals necessary for sustained T cell activation and proliferation (Lenschow et al, 1996;Sharpe and Freeman, 2002). Moreover, CD80 plays a role in the balance between immune activation and tolerance (Martıńez-Meńdez et al, 2021).…”

Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs

“…After hepatocarcinogenesis, immune cells are activated, and immune cells are supplied with energy in different ways. In pro-inflammatory cells, such as Th17 cells [64] and M1type macrophages [65], energy is produced through increased glycolysis exerting an antitumorigenic effect, whereas, in regulatory cells, such as Treg cells or M2-type macrophages, energy is produced through increased mitochondrial function and β-oxidation exerting its pro-tumorigenic effect [66,67].…”