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The NF-?B regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection.


ABSTRACT: Bcl-3 is an atypical member of the I?B family that acts in the nucleus to modulate transcription of many NF-?B 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.

SUBMITTER: Jaiswal H 

PROVIDER: S-EPMC7872245 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection.

Jaiswal Hemant H   Ciucci Thomas T   Wang Hongshan H   Tang Wanhu W   Claudio Estefania E   Murphy Philip M PM   Bosselut Rémy R   Siebenlist Ulrich U  

PLoS pathogens 20210128 1


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 vir  ...[more]

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