The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function
- Washington University in St. Louis, United States
- Osaka University, Japan
Abstract
BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during murine NK cell development, finding that it peaked in immature CD27+CD11b+ cells and decreased upon further maturation. Bach2 showed an organ and tissue-specific expression pattern in NK cells. Bach2 expression positively correlated with the expression of transcription factor TCF1 and negatively correlated with genes encoding NK effector molecules and those involved in the cell cycle. Lack of Bach2 expression caused changes in chromatin accessibility of corresponding genes. In the end, Bach2-deficiency resulted in increased proportions of terminally differentiated NK cells with increased production of granzymes and cytokines. NK cell-mediated control of tumor metastasis was also augmented in the absence of Bach2. Therefore, Bach2 is a key checkpoint protein regulating NK terminal maturation.
Data availability
RNA-sequencing data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE196530.ATAC-seq data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE212807.Previously published datasets are available on NCBI's Gene Expression Omnibus under the accession number GSE83978 and GSE77857.
-
Bach2 negatively regulates natural killer cell maturation and effector programNCBI Gene Expression Omnibus, GSE196530.
-
Chromatin accessibility of transcription factor Bach2 in mouse NK cells (ATAC-seq)NCBI Gene Expression Omnibus, GSE212807.
-
Memory-like CD8 T-cells sustain the immune response to chronic viral infectionsNCBI Gene Expression Omnibus, GSE83978.
-
BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancersNCBI Gene Expression Omnibus, GSE77857.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (R01-AI129545)
- Wayne M Yokoyama
National Human Genome Research Institute (R01-HG007175)
- Ting Wang
National Human Genome Research Institute (U01-HG009391)
- Ting Wang
National Human Genome Research Institute (U41-HG010972)
- Ting Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Gabrielle T Belz, The University of Queensland, Australia
Ethics
Animal experimentation: Mouse studies were conducted in accordance with the institutional ethical guidelines through institutional animal care and use committee (IACUC) protocol that was approved by the Animal Studies Committee of Washington University (#20180293).
Version history
- Received: January 24, 2022
- Preprint posted: February 14, 2022 (view preprint)
- Accepted: October 2, 2022
- Accepted Manuscript published: October 3, 2022 (version 1)
- Version of Record published: October 13, 2022 (version 2)
Copyright
© 2022, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,615
- views
-
- 325
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function
eLife 11:e77294.
https://doi.org/10.7554/eLife.77294
Further reading
-
- Immunology and Inflammation
The evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2’ C-terminus absence in Tp53−/− mice thymic lymphomas. However, the genomic stability effects of non-core regions from both Rag1c/c and Rag2c/c in BCR-ABL1+ B-lymphoblastic leukemia (BCR-ABL1+ B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remain unclear. Here, we established three mouse models of BCR-ABL1+ B-ALL in mice expressing full-length RAG (Ragf/f), core RAG1 (Rag1c/c), and core RAG2 (Rag2c/c). The Ragc/c (Rag1c/c and Rag2c/c) leukemia cells exhibited greater malignant tumor characteristics compared to Ragf/f cells. Additionally, Ragc/c cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than Ragf/f. We also revealed decreased RAG cleavage accuracy in Ragc/c cells and a smaller recombinant size in Rag1c/c cells, which could potentially exacerbate off-target V(D)J recombination in Ragc/c cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B-ALL.
-
- Cell Biology
- Immunology and Inflammation
Cytokine polyfunctionality is a well-established concept in immune cells, especially T cells, and their ability to concurrently produce multiple cytokines has been associated with better immunological disease control and subsequent effectiveness during infection and disease. To date, only little is known about the secretion dynamics of those cells, masked by the widespread deployment of mainly time-integrated endpoint measurement techniques that do not easily differentiate between concurrent and sequential secretion. Here, we employed a single-cell microfluidic platform capable of resolving the secretion dynamics of individual PBMCs. To study the dynamics of poly-cytokine secretion, as well as the dynamics of concurrent and sequential polyfunctionality, we analyzed the response at different time points after ex vivo activation. First, we observed the simultaneous secretion of cytokines over the measurement time for most stimulants in a subpopulation of cells only. Second, polyfunctionality generally decreased with prolonged stimulation times and revealed no correlation with the concentration of secreted cytokines in response to stimulation. However, we observed a general trend towards higher cytokine secretion in polyfunctional cells, with their secretion dynamics being distinctly different from mono-cytokine-secreting cells. This study provided insights into the distinct secretion behavior of heterogenous cell populations after stimulation with well-described agents and such a system could provide a better understanding of various immune dynamics in therapy and disease.
