Bob1 maintains T follicular helper cells for long-term humoral immunity

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Abstract

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

Abstract

Bob1 manages ICOS and cellular respiration in Tfh cells, ensuring the sustained generation of specific humoral responses. This likely contributes to persistent inflammation resulting from recurring allergen exposure.

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Most cited references 68

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T Follicular Helper Cell Biology: A Decade of Discovery and Diseases

Shane Crotty (2019)

Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage-defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers (the microanatomical sites of B cell mutation and antibody affinity maturation) and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years, particularly regarding their roles in a surprising range of diseases. Advances in the understanding of Tfh cell differentiation and function are discussed, as are the understanding of Tfh cells in infectious diseases, vaccines, autoimmune diseases, allergies, atherosclerosis, organ transplants, and cancer. This includes discussion of Tfh cells in the human immune system. Based on the discoveries to date, the next decade of Tfh research surely holds many more surprises. VIDEO ABSTRACT.

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Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.

Robert J Johnston, Amanda C Poholek, Daniel DiToro … (2009)

Effective B cell-mediated immunity and antibody responses often require help from CD4+ T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (T(FH)), provides this help; however, the molecular requirements for T(FH) differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo T(FH) differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits T(FH) differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that T(FH) cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in T(FH) differentiation.

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Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.

Akari Suzuki, Ryo Yamada, Xiaotian Chang … (2003)

Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

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Author and article information

Contributors

Shingo Ichimiya:

ORCID: http://orcid.org/0000-0003-2874-774X

ichimiya@sapmed.ac.jp

Journal

Journal ID (nlm-ta): Commun Biol

Journal ID (iso-abbrev): Commun Biol

Title: Communications Biology

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2399-3642

Publication date (Electronic): 15 February 2024

Publication date PMC-release: 15 February 2024

Publication date Collection: 2024

Volume: 7

Electronic Location Identifier: 185

Affiliations

[1 ]Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, ( https://ror.org/01h7cca57) Sapporo, 060-8556 Japan

[2 ]Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, ( https://ror.org/01h7cca57) Sapporo, 060-8556 Japan

[3 ]Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, ( https://ror.org/01h7cca57) Sapporo, 060-8556 Japan

[4 ]Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, ( https://ror.org/01h7cca57) Sapporo, 060-8556 Japan

[5 ]Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, ( https://ror.org/023rffy11) Kobe, 650-0047 Japan

[6 ]Department of Rehabilitation, Faculty of Healthcare and Science, Hokkaido Bunkyo University, ( https://ror.org/01rkrzs64) Eniwa, 061-1449 Japan

Author information

Masahiro Yanagi http://orcid.org/0000-0002-1851-4160

Ippei Ikegami http://orcid.org/0000-0001-5173-8249

Tatsuya Sato http://orcid.org/0000-0001-7876-1772

Taiki Sato http://orcid.org/0000-0002-6437-8630

Shiori Kamiya http://orcid.org/0000-0002-5371-4395

Takaya Abe http://orcid.org/0000-0001-5885-4875

Katsunori Shigehara http://orcid.org/0000-0001-9565-2068

Shingo Ichimiya http://orcid.org/0000-0003-2874-774X

Article

Publisher ID: 5827

DOI: 10.1038/s42003-024-05827-0

PMC ID: 10869348

PubMed ID: 38360857

SO-VID: 8b93260a-d3d8-4d5a-a886-12656befe126

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 July 2023

Date accepted : 16 January 2024

Funding

Funded by: FundRef https://doi.org/10.13039/501100001691, MEXT | Japan Society for the Promotion of Science (JSPS);

Award ID: 19K17778

Award ID: 21K08441

Award ID: 21K09610

Award ID: 21K09658

Award ID: 23H02695

Award Recipient : Shingo Ichimiya

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Keywords: antibodies,immunological memory,germinal centres,follicular t-helper cells

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Keywords: antibodies, immunological memory, germinal centres, follicular t-helper cells

Bob1 maintains T follicular helper cells for long-term humoral immunity

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Gamma Delta T cells

Most cited references 68

T Follicular Helper Cell Biology: A Decade of Discovery and Diseases

Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.

Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.

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