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Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ
Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127(−)KLRG1(+)) or memory precursors cells (MPECs, CD127(+)KLRG1(−)) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we sho...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884426/ https://www.ncbi.nlm.nih.gov/pubmed/33589606 http://dx.doi.org/10.1038/s41419-021-03470-9 |
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author | Jakic, Bojana Olson, William J. Siegmund, Kerstin Klepsch, Victoria Kimpel, Janine Labi, Verena Zehn, Dietmar Baier, Gottfried Hermann-Kleiter, Natascha |
author_facet | Jakic, Bojana Olson, William J. Siegmund, Kerstin Klepsch, Victoria Kimpel, Janine Labi, Verena Zehn, Dietmar Baier, Gottfried Hermann-Kleiter, Natascha |
author_sort | Jakic, Bojana |
collection | PubMed |
description | Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127(−)KLRG1(+)) or memory precursors cells (MPECs, CD127(+)KLRG1(−)) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8(+) memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-γ, TNFα, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6(−/−) OT-I T-cells showed that the augmented memory formation is CD8(+) T-cell intrinsic. Although the relative difference between the Nr2f6(+/+) and Nr2f6(−/−) OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-γ responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8(+) T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-γ mediated. IFN-γ blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8(+) T cells may have therapeutic potential for enhancing early IFN-γ production and consequently the functionality of memory CD8(+) T cells in vivo. |
format | Online Article Text |
id | pubmed-7884426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78844262021-02-25 Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ Jakic, Bojana Olson, William J. Siegmund, Kerstin Klepsch, Victoria Kimpel, Janine Labi, Verena Zehn, Dietmar Baier, Gottfried Hermann-Kleiter, Natascha Cell Death Dis Article Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127(−)KLRG1(+)) or memory precursors cells (MPECs, CD127(+)KLRG1(−)) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8(+) memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-γ, TNFα, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6(−/−) OT-I T-cells showed that the augmented memory formation is CD8(+) T-cell intrinsic. Although the relative difference between the Nr2f6(+/+) and Nr2f6(−/−) OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-γ responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8(+) T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-γ mediated. IFN-γ blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8(+) T cells may have therapeutic potential for enhancing early IFN-γ production and consequently the functionality of memory CD8(+) T cells in vivo. Nature Publishing Group UK 2021-02-15 /pmc/articles/PMC7884426/ /pubmed/33589606 http://dx.doi.org/10.1038/s41419-021-03470-9 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Jakic, Bojana Olson, William J. Siegmund, Kerstin Klepsch, Victoria Kimpel, Janine Labi, Verena Zehn, Dietmar Baier, Gottfried Hermann-Kleiter, Natascha Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title | Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title_full | Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title_fullStr | Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title_full_unstemmed | Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title_short | Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-γ |
title_sort | loss of the orphan nuclear receptor nr2f6 enhances cd8(+) t-cell memory via ifn-γ |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884426/ https://www.ncbi.nlm.nih.gov/pubmed/33589606 http://dx.doi.org/10.1038/s41419-021-03470-9 |
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