Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses

Ajay Abraham; Daniela Samaniego-Castruita; Isabella Han; Prathyaya Ramesh; Mi Thao Tran; Jillian Paladino; Heather Kligfeld; Roxroy C. Morgan; Rebecca L. Schmitz; Rebecca M. Southern; Ashima Shukla; Vipul Shukla

doi:10.1038/s41590-024-01920-y

Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses

Ajay Abraham, Daniela Samaniego-Castruita, Isabella Han, Prathyaya Ramesh, Mi Thao Tran, Jillian Paladino, Heather Kligfeld, Roxroy C. Morgan, Rebecca L. Schmitz, Rebecca M. Southern, Ashima Shukla, Vipul Shukla^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1β blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.

Original language	English (US)
Pages (from-to)	1704-1717
Number of pages	14
Journal	Nature Immunology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s41590-024-01920-y
State	Published - Sep 2024

Funding

We thank L. Arispe, S. Eisenbarth and W. Cui for critical reading of our paper and D. Kitamura at the Tokyo University of Science for sharing the 40LB cells. We thank X. Wang and M. Schipma and other members of the Northwestern University Sequencing Core for providing next-generation sequencing services, the Northwestern University RHLCCC Flow Cytometry Facility team (S. Swaminathan, C. Ostiguin, E. Dias and others) for their help with cell sorting and the Northwestern University Center for Advanced Microscopy (CAM) team members (C. Arvanitis and W. Liu) for helping with the imaging experiments. The RHLCCC Flow Cytometry Facility acknowledges support from the Cancer Center grant NCI CA060553, NIH 1S10OD011996-01 and 1S10OD026814-01. The CAM core acknowledges support from NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The schematics (Figs. , , , and and Extended Data Figs. , and ) were created using BioRender.com . R.C.M. is supported by The Ruth L. Kirschstein NRSA Institutional Research Training Grant (T32) (grant no. 5T32AI083216-15; Northwestern University Allergy and Immunology Research Program Training Grant, NUAIR). This work was supported by the R00 award from the National Cancer Institute (grant no. R00CA248835) and institutional startup funds from Northwestern University and the Lurie Cancer Center (to V.S.).

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-024-01920-y

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Abraham, A., Samaniego-Castruita, D., Han, I., Ramesh, P., Tran, M. T., Paladino, J., Kligfeld, H., Morgan, R. C., Schmitz, R. L., Southern, R. M., Shukla, A., & Shukla, V. (2024). Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses. Nature Immunology, 25(9), 1704-1717. https://doi.org/10.1038/s41590-024-01920-y

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title = "Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses",

abstract = "The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1β blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.",

author = "Ajay Abraham and Daniela Samaniego-Castruita and Isabella Han and Prathyaya Ramesh and Tran, {Mi Thao} and Jillian Paladino and Heather Kligfeld and Morgan, {Roxroy C.} and Schmitz, {Rebecca L.} and Southern, {Rebecca M.} and Ashima Shukla and Vipul Shukla",

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Abraham, A, Samaniego-Castruita, D, Han, I, Ramesh, P, Tran, MT, Paladino, J, Kligfeld, H, Morgan, RC, Schmitz, RL, Southern, RM, Shukla, A & Shukla, V 2024, 'Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses', Nature Immunology, vol. 25, no. 9, pp. 1704-1717. https://doi.org/10.1038/s41590-024-01920-y

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AU - Han, Isabella

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AU - Tran, Mi Thao

AU - Paladino, Jillian

AU - Kligfeld, Heather

AU - Morgan, Roxroy C.

AU - Schmitz, Rebecca L.

AU - Southern, Rebecca M.

AU - Shukla, Ashima

AU - Shukla, Vipul

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AB - The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1β blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.

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Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses

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