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Dynamical Analysis of the Regulatory Network Controlling Natural Killer Cells Differentiation.

ABSTRACT: Many disease fighting strategies have focused on the generation of NK cells, since they constitute the main immune barrier against cancer and intracellular pathogens such as viruses. Therefore, a predictive model for the development of NK cells would constitute a useful tool to test several hypotheses regarding the production of these cells during both physiological and pathological conditions. Here, we present a boolean network model that reproduces experimental results reported on the literature regarding the progressive stages of the development of NK cells in wild-type and mutant backgrounds. The model allows for the simulation of different conditions, including extracellular micro-environment as well as the simulation of genetic alterations. It also describes how NK cell differentiation depends on a molecular regulatory network that controls the specification of lymphoid lineages, such as T and B cells, which share a common progenitor with NKs. Furthermore, the study shows that the structure of the regulatory network strongly determines the stability of the expression patterns against perturbations.

SUBMITTER: Liquitaya-Montiel AJ

PROVIDER: S-EPMC6082967 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dynamical Analysis of the Regulatory Network Controlling Natural Killer Cells Differentiation.

Liquitaya-Montiel Adhemar J AJ Mendoza Luis L

Frontiers in physiology 20180802

Many disease fighting strategies have focused on the generation of NK cells, since they constitute the main immune barrier against cancer and intracellular pathogens such as viruses. Therefore, a predictive model for the development of NK cells would constitute a useful tool to test several hypotheses regarding the production of these cells during both physiological and pathological conditions. Here, we present a boolean network model that reproduces experimental results reported on the literatu ...[more]

PMID: 30116200

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Project description:BackgroundCytomegalovirus establishes lifelong persistency in the host and leads to life threatening situations in immunocompromised patients. FoxP3+ T regulatory cells (Tregs) critically control and suppress innate and adaptive immune responses. However, their specific role during MCMV infection, especially pertaining to their interaction with NK cells, remains incompletely defined.MethodsTo understand the contribution of Tregs on NK cell function during acute MCMV infection, we infected Treg depleted and undepleted DEREG mice with WT MCMV and examined Treg and NK cell frequency, number, activation and effector function in vivo.ResultsOur results reveal an increased frequency of activated Tregs within the CD4+ T cell population shortly after MCMV infection. Specific depletion of Tregs in DEREG mice under homeostatic conditions leads to an increase in NK cell number as well as to a higher activation status of these cells as compared with non-depleted controls. Interestingly, upon infection this effect on NK cells is completely neutralized in terms of cell frequency, CD69 expression and functionality with respect to IFN-? production. Furthermore, composition of the NK cell population with regard to Ly49H expression remains unchanged. In contrast, absence of Tregs still boosts the general T cell response upon infection to a level comparable to the enhanced activation seen in uninfected mice. CD4+ T cells especially benefit from Treg depletion exhibiting a two-fold increase of CD69+ cells 40 h and IFN-?+ cells 7 days p.i. while, MCMV infection per se induces robust CD8+ T cell activation which is also further augmented in Treg-depleted mice. Nevertheless, the viral burden in the liver and spleen remain unaltered upon Treg ablation during the course of infection.ConclusionsThus, MCMV infection abolishes Treg suppressing effects on NK cells whereas T cells benefit from their absence during acute infection. This study provides novel information in understanding the collaborative interaction between NK cells and Tregs during a viral infection and provides further knowledge that could be adopted in therapeutic setups to improve current treatment of organ transplant patients where modulation of Tregs is envisioned as a strategy to overcome transplant rejection.

Dataset Information

Dynamical Analysis of the Regulatory Network Controlling Natural Killer Cells Differentiation.

Publications

Dynamical Analysis of the Regulatory Network Controlling Natural Killer Cells Differentiation.

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