Cargando…
The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts
The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream target...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005848/ https://www.ncbi.nlm.nih.gov/pubmed/29946322 http://dx.doi.org/10.3389/fimmu.2018.01338 |
_version_ | 1783332737437925376 |
---|---|
author | Baur, Johannes Otto, Christoph Steger, Ulrich Klein-Hessling, Stefan Muhammad, Khalid Pusch, Tobias Murti, Krisna Wismer, Rhoda Germer, Christoph-Thomas Klein, Ingo Müller, Nora Serfling, Edgar Avots, Andris |
author_facet | Baur, Johannes Otto, Christoph Steger, Ulrich Klein-Hessling, Stefan Muhammad, Khalid Pusch, Tobias Murti, Krisna Wismer, Rhoda Germer, Christoph-Thomas Klein, Ingo Müller, Nora Serfling, Edgar Avots, Andris |
author_sort | Baur, Johannes |
collection | PubMed |
description | The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8(+) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation. |
format | Online Article Text |
id | pubmed-6005848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60058482018-06-26 The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts Baur, Johannes Otto, Christoph Steger, Ulrich Klein-Hessling, Stefan Muhammad, Khalid Pusch, Tobias Murti, Krisna Wismer, Rhoda Germer, Christoph-Thomas Klein, Ingo Müller, Nora Serfling, Edgar Avots, Andris Front Immunol Immunology The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8(+) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation. Frontiers Media S.A. 2018-06-12 /pmc/articles/PMC6005848/ /pubmed/29946322 http://dx.doi.org/10.3389/fimmu.2018.01338 Text en Copyright © 2018 Baur, Otto, Steger, Klein-Hessling, Muhammad, Pusch, Murti, Wismer, Germer, Klein, Müller, Serfling and Avots. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Baur, Johannes Otto, Christoph Steger, Ulrich Klein-Hessling, Stefan Muhammad, Khalid Pusch, Tobias Murti, Krisna Wismer, Rhoda Germer, Christoph-Thomas Klein, Ingo Müller, Nora Serfling, Edgar Avots, Andris The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title | The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title_full | The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title_fullStr | The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title_full_unstemmed | The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title_short | The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts |
title_sort | transcription factor nfatc1 supports the rejection of heterotopic heart allografts |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005848/ https://www.ncbi.nlm.nih.gov/pubmed/29946322 http://dx.doi.org/10.3389/fimmu.2018.01338 |
work_keys_str_mv | AT baurjohannes thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT ottochristoph thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT stegerulrich thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT kleinhesslingstefan thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT muhammadkhalid thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT puschtobias thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT murtikrisna thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT wismerrhoda thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT germerchristophthomas thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT kleiningo thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT mullernora thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT serflingedgar thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT avotsandris thetranscriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT baurjohannes transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT ottochristoph transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT stegerulrich transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT kleinhesslingstefan transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT muhammadkhalid transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT puschtobias transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT murtikrisna transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT wismerrhoda transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT germerchristophthomas transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT kleiningo transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT mullernora transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT serflingedgar transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts AT avotsandris transcriptionfactornfatc1supportstherejectionofheterotopicheartallografts |