PU.1 and BCL11B sequentially cooperate with RUNX1 to anchor mSWI/SNF to poise the T cell effector landscape
Open accessAbstract
Adaptive immunity relies on specialized effector functions elicited by lymphocytes, yet how antigen recognition activates appropriate effector responses through nonspecific signaling intermediates is unclear. Here we examined the role of chromatin priming in specifying the functional outputs of effector T cells and found that most of the cis-regulatory landscape active in effector T cells was poised early in development before the expression of the T cell antigen receptor. We identified two principal mechanisms underpinning this poised landscape: the recruitment of the nucleosome remodeler mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) by the transcription factors RUNX1 and PU.1 to establish chromatin accessibility at T effector loci; and a 'relay' whereby the transcription factor BCL11B succeeded PU.1 to maintain occupancy of the chromatin remodeling complex mSWI/SNF together with RUNX1, after PU.1 silencing during lineage commitment. These mechanisms define modes by which T cells acquire the potential to elicit specialized effector functions early in their ontogeny and underscore the importance of integrating extrinsic cues to the developmentally specified intrinsic program.
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- Authors
- Gamble, N., Bradu, A., Caldwell, J. A., McKeever, J., Bolonduro, O., Ermis, E., Kaiser, C., Kim, Y., Parks, B., Klemm, S., Greenleaf, W. J., Crabtree, G. R., & Koh, A. S.
- Affiliations
- University of Chicago (US)
- Stanford University (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Stanford Medicine (US)
- Corresponding author
- Koh, Andrew S.
- ORCID
- Venue
- Nature Immunology
- Published
- 2024-04-17
- Volume
- 25
- Issue
- 5
- Pages
- 860-872
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC11089574
- OpenAlex
- W4394881898
- Cited by
- 26
- References
- 7
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 4
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-05-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35-GM138150, T32-GM139782)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (T32-AI07090)
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (CA-163915)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- effector T cell differentiation, chromatin accessibility, PU.1, RUNX1, BCL11B, transcription factor cooperation, T cell precursors, lineage commitment, cis-regulatory elements, nucleosome remodeling, T cell ontogeny
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Chromosomal Proteins, Non-Histone, Mice, Inbred C57BL, Proto-Oncogene Proteins, Repressor Proteins, T-Lymphocytes, Transcription Factors, Trans-Activators, Mice, Knockout, Tumor Suppressor Proteins, Chromatin Assembly and Disassembly, Core Binding Factor Alpha 2 Subunit, Mice
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