期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 219, 期 2, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20211406
关键词
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资金
- Swedish Research Council [2017-01118, 2018-05973, SNIC 2019/8-289, 2020/16-34]
- Cancerfonden [CAN 2018/710]
- Ake Wiberg Stiftelse [M18-0094]
- Austrian Science Fund [P28841]
- Wenner-Gren Foundation
- German Research Foundation [RE 4264/1-1, DU 1964/1-1]
- European Research Council under the European Union [740349]
- Ministry of Science and Higher Education of the Russian Federation [075-15-2020-784]
- Austrian Science Fund
- Swedish Research Council [2017-01118] Funding Source: Swedish Research Council
- European Research Council (ERC) [740349] Funding Source: European Research Council (ERC)
- Formas [2017-01118] Funding Source: Formas
The transcription factor Bhlhe40 plays a crucial negative regulatory role in the germinal center reaction by affecting both B cells and T follicular helper cells intrinsically, leading to a dysregulated germinal center response and potential lymphomagenesis in its absence.
The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (T-FH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of T-FH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal T-FH cells in various tissues. The transcription factor Bhlhe40 restrains the germinal center reaction through cell-intrinsic functions in both activated B cells and T follicular helper cells. The absence of Bhlhe40 results in a dysregulated germinal center response and lymphomagenesis.
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