Continuous Modeling of T CD4 Lymphocyte Activation and Function

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 reinf...

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Autores principales:	David Martínez-Méndez, Luis Mendoza, Carlos Villarreal, Leonor Huerta
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	T CD4 cells metabolism T cell receptor lymphocyte activation CTLA-4 mTOR Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/e7fbf93c4663418ca799bb877e699bf5
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spelling	oai:doaj.org-article:e7fbf93c4663418ca799bb877e699bf52021-11-05T06:39:23ZContinuous Modeling of T CD4 Lymphocyte Activation and Function1664-322410.3389/fimmu.2021.743559https://doaj.org/article/e7fbf93c4663418ca799bb877e699bf52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.743559/fullhttps://doaj.org/toc/1664-3224T 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.David Martínez-MéndezLuis MendozaLuis MendozaCarlos VillarrealCarlos VillarrealLeonor HuertaFrontiers Media S.A.articleT CD4 cellsmetabolismT cell receptorlymphocyte activationCTLA-4mTORImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	T CD4 cells metabolism T cell receptor lymphocyte activation CTLA-4 mTOR Immunologic diseases. Allergy RC581-607
spellingShingle	T CD4 cells metabolism T cell receptor lymphocyte activation CTLA-4 mTOR Immunologic diseases. Allergy RC581-607 David Martínez-Méndez Luis Mendoza Luis Mendoza Carlos Villarreal Carlos Villarreal Leonor Huerta Continuous Modeling of T CD4 Lymphocyte Activation and Function
description	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.
format	article
author	David Martínez-Méndez Luis Mendoza Luis Mendoza Carlos Villarreal Carlos Villarreal Leonor Huerta
author_facet	David Martínez-Méndez Luis Mendoza Luis Mendoza Carlos Villarreal Carlos Villarreal Leonor Huerta
author_sort	David Martínez-Méndez
title	Continuous Modeling of T CD4 Lymphocyte Activation and Function
title_short	Continuous Modeling of T CD4 Lymphocyte Activation and Function
title_full	Continuous Modeling of T CD4 Lymphocyte Activation and Function
title_fullStr	Continuous Modeling of T CD4 Lymphocyte Activation and Function
title_full_unstemmed	Continuous Modeling of T CD4 Lymphocyte Activation and Function
title_sort	continuous modeling of t cd4 lymphocyte activation and function
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e7fbf93c4663418ca799bb877e699bf5
work_keys_str_mv	AT davidmartinezmendez continuousmodelingoftcd4lymphocyteactivationandfunction AT luismendoza continuousmodelingoftcd4lymphocyteactivationandfunction AT luismendoza continuousmodelingoftcd4lymphocyteactivationandfunction AT carlosvillarreal continuousmodelingoftcd4lymphocyteactivationandfunction AT carlosvillarreal continuousmodelingoftcd4lymphocyteactivationandfunction AT leonorhuerta continuousmodelingoftcd4lymphocyteactivationandfunction
_version_	1718444503539384320

Continuous Modeling of T CD4 Lymphocyte Activation and Function

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