Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response
Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin‐2 (IL‐2) signaling in a population of T cells during an immune response by combining in silico model...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2010-01-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb.2010.90 |
| _version_ | 1797281813184380928 |
|---|---|
| author | Ofer Feinerman Garrit Jentsch Karen E Tkach Jesse W Coward Matthew M Hathorn Michael W Sneddon Thierry Emonet Kendall A Smith Grégoire Altan‐Bonnet |
| author_facet | Ofer Feinerman Garrit Jentsch Karen E Tkach Jesse W Coward Matthew M Hathorn Michael W Sneddon Thierry Emonet Kendall A Smith Grégoire Altan‐Bonnet |
| author_sort | Ofer Feinerman |
| collection | DOAJ |
| description | Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin‐2 (IL‐2) signaling in a population of T cells during an immune response by combining in silico modeling and single‐cell measurements in vitro. We demonstrate that IL‐2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL‐2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug‐of‐war for IL‐2 between regulatory (Treg) and effector (Teff) T cells, whereby access to IL‐2 can either increase the survival of Teff cells or the suppressive capacity of Treg cells. This tug‐of‐war is the mechanism enforcing, at the systems level, a core function of Treg cells, namely the specific suppression of survival signals for weakly activated Teff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of Treg suppression. |
| first_indexed | 2024-03-07T17:02:52Z |
| format | Article |
| id | doaj.art-662b3f76a4324301a3cabe5e7129ddcd |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T17:02:52Z |
| publishDate | 2010-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-662b3f76a4324301a3cabe5e7129ddcd2024-03-03T03:11:51ZengSpringer NatureMolecular Systems Biology1744-42922010-01-0161n/an/a10.1038/msb.2010.90Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune responseOfer Feinerman0Garrit Jentsch1Karen E Tkach2Jesse W Coward3Matthew M Hathorn4Michael W Sneddon5Thierry Emonet6Kendall A Smith7Grégoire Altan‐Bonnet8ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan‐Kettering Cancer Center New York NY USADepartment of Molecular, Cellular, and Developmental Biology, Yale University New Haven CT USAImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan‐Kettering Cancer Center New York NY USAImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan‐Kettering Cancer Center New York NY USAImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan‐Kettering Cancer Center New York NY USADepartment of Molecular, Cellular, and Developmental Biology, Yale University New Haven CT USADepartment of Molecular, Cellular, and Developmental Biology, Yale University New Haven CT USADivision of Immunology, Department of Medicine, Weill Medical College, Cornell University New York NY USAImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan‐Kettering Cancer Center New York NY USAUnderstanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin‐2 (IL‐2) signaling in a population of T cells during an immune response by combining in silico modeling and single‐cell measurements in vitro. We demonstrate that IL‐2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL‐2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug‐of‐war for IL‐2 between regulatory (Treg) and effector (Teff) T cells, whereby access to IL‐2 can either increase the survival of Teff cells or the suppressive capacity of Treg cells. This tug‐of‐war is the mechanism enforcing, at the systems level, a core function of Treg cells, namely the specific suppression of survival signals for weakly activated Teff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of Treg suppression.https://doi.org/10.1038/msb.2010.90cellular heterogeneitycomputer modelingIL‐2 signalingimmunologyregulatory T cells |
| spellingShingle | Ofer Feinerman Garrit Jentsch Karen E Tkach Jesse W Coward Matthew M Hathorn Michael W Sneddon Thierry Emonet Kendall A Smith Grégoire Altan‐Bonnet Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response Molecular Systems Biology cellular heterogeneity computer modeling IL‐2 signaling immunology regulatory T cells |
| title | Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response |
| title_full | Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response |
| title_fullStr | Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response |
| title_full_unstemmed | Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response |
| title_short | Single‐cell quantification of IL‐2 response by effector and regulatory T cells reveals critical plasticity in immune response |
| title_sort | single cell quantification of il 2 response by effector and regulatory t cells reveals critical plasticity in immune response |
| topic | cellular heterogeneity computer modeling IL‐2 signaling immunology regulatory T cells |
| url | https://doi.org/10.1038/msb.2010.90 |
| work_keys_str_mv | AT oferfeinerman singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT garritjentsch singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT karenetkach singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT jessewcoward singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT matthewmhathorn singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT michaelwsneddon singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT thierryemonet singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT kendallasmith singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse AT gregoirealtanbonnet singlecellquantificationofil2responsebyeffectorandregulatorytcellsrevealscriticalplasticityinimmuneresponse |