Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy
Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytoki...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/57417 |
| _version_ | 1811180591405596672 |
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| author | Julie Y Zhou Carlos A Alvarez Brian A Cobb |
| author_facet | Julie Y Zhou Carlos A Alvarez Brian A Cobb |
| author_sort | Julie Y Zhou |
| collection | DOAJ |
| description | Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines. |
| first_indexed | 2024-04-11T09:05:53Z |
| format | Article |
| id | doaj.art-2ae5ce3586bd49bba8f5b411902047ae |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:05:53Z |
| publishDate | 2021-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2ae5ce3586bd49bba8f5b411902047ae2022-12-22T04:32:39ZengeLife Sciences Publications LtdeLife2050-084X2021-02-011010.7554/eLife.57417Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacyJulie Y Zhou0https://orcid.org/0000-0002-1533-5183Carlos A Alvarez1Brian A Cobb2https://orcid.org/0000-0003-1055-2530Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, United StatesDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, United StatesDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, United StatesCells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.https://elifesciences.org/articles/57417cytokineTregSTAT5STAT6interleukin-4interleukin-2 |
| spellingShingle | Julie Y Zhou Carlos A Alvarez Brian A Cobb Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy eLife cytokine Treg STAT5 STAT6 interleukin-4 interleukin-2 |
| title | Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy |
| title_full | Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy |
| title_fullStr | Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy |
| title_full_unstemmed | Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy |
| title_short | Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy |
| title_sort | integration of il 2 and il 4 signals coordinates divergent regulatory t cell responses and drives therapeutic efficacy |
| topic | cytokine Treg STAT5 STAT6 interleukin-4 interleukin-2 |
| url | https://elifesciences.org/articles/57417 |
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