Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration
IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 a...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Association of Immunologists
2015
|
| Online Access: | http://hdl.handle.net/1721.1/99480 https://orcid.org/0000-0002-1545-1651 |
| _version_ | 1826217744244146176 |
|---|---|
| author | Arneja, Abhinav Johnson, Hannah Gabrovsek, Laura White, Forest M. Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Arneja, Abhinav Johnson, Hannah Gabrovsek, Laura White, Forest M. Lauffenburger, Douglas A |
| author_sort | Arneja, Abhinav |
| collection | MIT |
| description | IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 and IL-15 trigger distinct phenotypes in T cells remain elusive. To elucidate these mechanisms, we performed a quantitative comparison of the phosphotyrosine signaling network and resulting phenotypes triggered by IL-2 and IL-15. This study revealed that the signaling networks activated by IL-2 or IL-15 are highly similar and that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Distinct phenotypes associated with IL-2 or IL-15 stimulation therefore arise through differential regulation of IL-2/15R signal strength and duration because of differences in cytokine–receptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokine–receptor intracellular trafficking kinetics. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases. |
| first_indexed | 2024-09-23T17:08:27Z |
| format | Article |
| id | mit-1721.1/99480 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:08:27Z |
| publishDate | 2015 |
| publisher | American Association of Immunologists |
| record_format | dspace |
| spelling | mit-1721.1/994802022-09-29T23:54:49Z Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration Arneja, Abhinav Johnson, Hannah Gabrovsek, Laura White, Forest M. Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Arneja, Abhinav Johnson, Hannah Gabrovsek, Laura Lauffenburger, Douglas A. White, Forest M. IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 and IL-15 trigger distinct phenotypes in T cells remain elusive. To elucidate these mechanisms, we performed a quantitative comparison of the phosphotyrosine signaling network and resulting phenotypes triggered by IL-2 and IL-15. This study revealed that the signaling networks activated by IL-2 or IL-15 are highly similar and that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Distinct phenotypes associated with IL-2 or IL-15 stimulation therefore arise through differential regulation of IL-2/15R signal strength and duration because of differences in cytokine–receptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokine–receptor intracellular trafficking kinetics. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases. National Institutes of Health (U.S.) (Grant U54CA11927) National Institutes of Health (U.S.) (Grant R01 AI065824) United States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-0001) 2015-10-27T17:50:06Z 2015-10-27T17:50:06Z 2013-12 2013-09 Article http://purl.org/eprint/type/JournalArticle 0022-1767 1550-6606 http://hdl.handle.net/1721.1/99480 Arneja, A., H. Johnson, L. Gabrovsek, D. A. Lauffenburger, and F. M. White. “Qualitatively Different T Cell Phenotypic Responses to IL-2 Versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration.” The Journal of Immunology 192, no. 1 (December 2, 2013): 123–135. https://orcid.org/0000-0002-1545-1651 en_US http://dx.doi.org/10.4049/jimmunol.1302291 The Journal of Immunology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association of Immunologists PMC |
| spellingShingle | Arneja, Abhinav Johnson, Hannah Gabrovsek, Laura White, Forest M. Lauffenburger, Douglas A Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title | Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title_full | Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title_fullStr | Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title_full_unstemmed | Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title_short | Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration |
| title_sort | qualitatively different t cell phenotypic responses to il 2 versus il 15 are unified by identical dependences on receptor signal strength and duration |
| url | http://hdl.handle.net/1721.1/99480 https://orcid.org/0000-0002-1545-1651 |
| work_keys_str_mv | AT arnejaabhinav qualitativelydifferenttcellphenotypicresponsestoil2versusil15areunifiedbyidenticaldependencesonreceptorsignalstrengthandduration AT johnsonhannah qualitativelydifferenttcellphenotypicresponsestoil2versusil15areunifiedbyidenticaldependencesonreceptorsignalstrengthandduration AT gabrovseklaura qualitativelydifferenttcellphenotypicresponsestoil2versusil15areunifiedbyidenticaldependencesonreceptorsignalstrengthandduration AT whiteforestm qualitativelydifferenttcellphenotypicresponsestoil2versusil15areunifiedbyidenticaldependencesonreceptorsignalstrengthandduration AT lauffenburgerdouglasa qualitativelydifferenttcellphenotypicresponsestoil2versusil15areunifiedbyidenticaldependencesonreceptorsignalstrengthandduration |