Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions.
Optimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3887105?pdf=render |
| _version_ | 1818509634780004352 |
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| author | Mithun Khattar Yoshihiro Miyahara Paul M Schroder Aini Xie Wenhao Chen Stanislaw M Stepkowski |
| author_facet | Mithun Khattar Yoshihiro Miyahara Paul M Schroder Aini Xie Wenhao Chen Stanislaw M Stepkowski |
| author_sort | Mithun Khattar |
| collection | DOAJ |
| description | Optimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory role in promoting their survival and proliferation, IL-2 has been considered as a selective therapeutic target for preventing T cell mediated diseases. However, in order to further explore IL-2 targeted therapy, it is critical to precisely understand its role during early events of T cell activation. In this study, we delineate the role of IL-2 and other γc cytokines in promoting the survival of CD4 and CD8 T cells during early phases of priming. Under IL-2 inhibitory conditions (by neutralizing anti-IL-2 mAbs), the survival of activated CD8⁺ T cells was reduced, whereas CD4⁺ T cells remained much more resistant. These results correlated with reduced Bcl-2 expression, and mitochondrial membrane potential in CD8⁺ T cells in comparison to CD4⁺ T cells. However, using transwell co-culture assays we have found that CD4⁺ T cells could rescue the survival of CD8⁺ T cells even under IL-2 deprived conditions via secretion of soluble factors. A cytokine screen performed on CD8⁺ T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation. Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4⁺ and CD8⁺ T cells. Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses. Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses. |
| first_indexed | 2024-12-10T22:48:05Z |
| format | Article |
| id | doaj.art-dfc770baab604d759e9b2c8410d641e7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T22:48:05Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dfc770baab604d759e9b2c8410d641e72022-12-22T01:30:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8588210.1371/journal.pone.0085882Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions.Mithun KhattarYoshihiro MiyaharaPaul M SchroderAini XieWenhao ChenStanislaw M StepkowskiOptimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory role in promoting their survival and proliferation, IL-2 has been considered as a selective therapeutic target for preventing T cell mediated diseases. However, in order to further explore IL-2 targeted therapy, it is critical to precisely understand its role during early events of T cell activation. In this study, we delineate the role of IL-2 and other γc cytokines in promoting the survival of CD4 and CD8 T cells during early phases of priming. Under IL-2 inhibitory conditions (by neutralizing anti-IL-2 mAbs), the survival of activated CD8⁺ T cells was reduced, whereas CD4⁺ T cells remained much more resistant. These results correlated with reduced Bcl-2 expression, and mitochondrial membrane potential in CD8⁺ T cells in comparison to CD4⁺ T cells. However, using transwell co-culture assays we have found that CD4⁺ T cells could rescue the survival of CD8⁺ T cells even under IL-2 deprived conditions via secretion of soluble factors. A cytokine screen performed on CD8⁺ T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation. Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4⁺ and CD8⁺ T cells. Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses. Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses.http://europepmc.org/articles/PMC3887105?pdf=render |
| spellingShingle | Mithun Khattar Yoshihiro Miyahara Paul M Schroder Aini Xie Wenhao Chen Stanislaw M Stepkowski Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. PLoS ONE |
| title | Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. |
| title_full | Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. |
| title_fullStr | Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. |
| title_full_unstemmed | Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. |
| title_short | Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. |
| title_sort | interleukin 21 is a critical regulator of cd4 and cd8 t cell survival during priming under interleukin 2 deprivation conditions |
| url | http://europepmc.org/articles/PMC3887105?pdf=render |
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