Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation.
Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level ha...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC3772054?pdf=render |
| _version_ | 1811217128837087232 |
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| author | Yun M Zhao Anthony R French |
| author_facet | Yun M Zhao Anthony R French |
| author_sort | Yun M Zhao |
| collection | DOAJ |
| description | Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation. |
| first_indexed | 2024-04-12T06:50:09Z |
| format | Article |
| id | doaj.art-40d2a3c2c7e24e9593b60f380aa1d7bb |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T06:50:09Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-40d2a3c2c7e24e9593b60f380aa1d7bb2022-12-22T03:43:24ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582013-01-0199e100322210.1371/journal.pcbi.1003222Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation.Yun M ZhaoAnthony R FrenchNatural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation.http://europepmc.org/articles/PMC3772054?pdf=render |
| spellingShingle | Yun M Zhao Anthony R French Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. PLoS Computational Biology |
| title | Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. |
| title_full | Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. |
| title_fullStr | Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. |
| title_full_unstemmed | Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. |
| title_short | Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. |
| title_sort | mechanistic model of natural killer cell proliferative response to il 15 receptor stimulation |
| url | http://europepmc.org/articles/PMC3772054?pdf=render |
| work_keys_str_mv | AT yunmzhao mechanisticmodelofnaturalkillercellproliferativeresponsetoil15receptorstimulation AT anthonyrfrench mechanisticmodelofnaturalkillercellproliferativeresponsetoil15receptorstimulation |