Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation
Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which neces...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.962175/full |
| _version_ | 1811266029854130176 |
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| author | David Martínez-Méndez Leonor Huerta Carlos Villarreal |
| author_facet | David Martínez-Méndez Leonor Huerta Carlos Villarreal |
| author_sort | David Martínez-Méndez |
| collection | DOAJ |
| description | Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the TFH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or TFH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression. |
| first_indexed | 2024-04-12T20:34:37Z |
| format | Article |
| id | doaj.art-2cd4268fd89b409ab0b23610c4c58829 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T20:34:37Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2cd4268fd89b409ab0b23610c4c588292022-12-22T03:17:37ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.962175962175Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiationDavid Martínez-Méndez0Leonor Huerta1Carlos Villarreal2Instituto de Física, Universidad Nacional Autónoma de México, Mexico City, MexicoInstituto de Investigaciones Biomédicas, Departamento de Inmunología, Universidad Nacional Autónoma de México, Mexico City, MexicoInstituto de Física, Universidad Nacional Autónoma de México, Mexico City, MexicoUpon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the TFH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or TFH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression.https://www.frontiersin.org/articles/10.3389/fimmu.2022.962175/fullCD4+ T cellslymphocytesmathematical modelmetabolismnutrientshypoxia |
| spellingShingle | David Martínez-Méndez Leonor Huerta Carlos Villarreal Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation Frontiers in Immunology CD4+ T cells lymphocytes mathematical model metabolism nutrients hypoxia |
| title | Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation |
| title_full | Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation |
| title_fullStr | Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation |
| title_full_unstemmed | Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation |
| title_short | Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation |
| title_sort | modeling the effect of environmental cytokines nutrient conditions and hypoxia on cd4 t cell differentiation |
| topic | CD4+ T cells lymphocytes mathematical model metabolism nutrients hypoxia |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.962175/full |
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