The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection.
Bcl-3 is an atypical member of the IκB family that acts in the nucleus to modulate transcription of many NF-κB targets in a highly context-dependent manner. Accordingly, complete Bcl-3-/- mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009249&type=printable |
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| author | Hemant Jaiswal Thomas Ciucci Hongshan Wang Wanhu Tang Estefania Claudio Philip M Murphy Rémy Bosselut Ulrich Siebenlist |
| author_facet | Hemant Jaiswal Thomas Ciucci Hongshan Wang Wanhu Tang Estefania Claudio Philip M Murphy Rémy Bosselut Ulrich Siebenlist |
| author_sort | Hemant Jaiswal |
| collection | DOAJ |
| description | Bcl-3 is an atypical member of the IκB family that acts in the nucleus to modulate transcription of many NF-κB targets in a highly context-dependent manner. Accordingly, complete Bcl-3-/- mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action in individual immune cell types have not been clearly defined. Here, we document a cell-autonomous role for Bcl-3 in CD8+ T cell differentiation during the response to lymphocytic choriomeningitis virus infection. Single-cell RNA-seq and flow cytometric analysis of virus-specific Bcl3-/- CD8+ T cells revealed that differentiation was skewed towards terminal effector cells at the expense of memory precursor effector cells (MPECs). Accordingly, Bcl3-/- CD8+ T cells exhibited reduced memory cell formation and a defective recall response. Conversely, Bcl-3-overexpression in transgenic CD8+ T cells enhanced MPEC formation but reduced effector cell differentiation. Together, our results establish Bcl-3 as an autonomous determinant of memory/terminal effector cell balance during CD8+ T cell differentiation in response to acute viral infection. Our results provide proof-of-principle for targeting Bcl-3 pharmacologically to optimize adaptive immune responses to infectious agents, cancer cells, vaccines and other stimuli that induce CD8+ T cell differentiation. |
| format | Article |
| id | doaj-art-ef2eb82acd264a7fb7589d5ab6025ba3 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-ef2eb82acd264a7fb7589d5ab6025ba32025-08-20T02:23:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-01-01171e100924910.1371/journal.ppat.1009249The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection.Hemant JaiswalThomas CiucciHongshan WangWanhu TangEstefania ClaudioPhilip M MurphyRémy BosselutUlrich SiebenlistBcl-3 is an atypical member of the IκB family that acts in the nucleus to modulate transcription of many NF-κB targets in a highly context-dependent manner. Accordingly, complete Bcl-3-/- mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action in individual immune cell types have not been clearly defined. Here, we document a cell-autonomous role for Bcl-3 in CD8+ T cell differentiation during the response to lymphocytic choriomeningitis virus infection. Single-cell RNA-seq and flow cytometric analysis of virus-specific Bcl3-/- CD8+ T cells revealed that differentiation was skewed towards terminal effector cells at the expense of memory precursor effector cells (MPECs). Accordingly, Bcl3-/- CD8+ T cells exhibited reduced memory cell formation and a defective recall response. Conversely, Bcl-3-overexpression in transgenic CD8+ T cells enhanced MPEC formation but reduced effector cell differentiation. Together, our results establish Bcl-3 as an autonomous determinant of memory/terminal effector cell balance during CD8+ T cell differentiation in response to acute viral infection. Our results provide proof-of-principle for targeting Bcl-3 pharmacologically to optimize adaptive immune responses to infectious agents, cancer cells, vaccines and other stimuli that induce CD8+ T cell differentiation.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009249&type=printable |
| spellingShingle | Hemant Jaiswal Thomas Ciucci Hongshan Wang Wanhu Tang Estefania Claudio Philip M Murphy Rémy Bosselut Ulrich Siebenlist The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. PLoS Pathogens |
| title | The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. |
| title_full | The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. |
| title_fullStr | The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. |
| title_full_unstemmed | The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. |
| title_short | The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection. |
| title_sort | nf κb regulator bcl 3 restricts terminal differentiation and promotes memory cell formation of cd8 t cells during viral infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009249&type=printable |
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