TFEB activation hallmarks antigenic experience of B lymphocytes and directs germinal center fate decisions

Matthias Münchhalfen, Richard Görg, Michael Haberl, Jens Löber, Jakob Willenbrink, Laura Schwarzt, Charlotte Höltermann, Christian Ickes, Leonard Hammermann, Jan Kus, Björn Chapuy, Andrea Ballabio, Sybille D. Reichardt, Alexander Flügel, Niklas Engels and Jürgen Wienands ()
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Matthias Münchhalfen: University Medical Center Göttingen
Richard Görg: University Medical Center Göttingen
Michael Haberl: University Medical Center Göttingen
Jens Löber: University Medical Center Göttingen
Jakob Willenbrink: University Medical Center Göttingen
Laura Schwarzt: University Medical Center Göttingen
Charlotte Höltermann: University Medical Center Göttingen
Christian Ickes: University Medical Center Göttingen, Georg August University
Leonard Hammermann: University Medical Center Göttingen
Jan Kus: University Medical Center Göttingen
Björn Chapuy: University Medical Center Göttingen
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
Sybille D. Reichardt: University Medical Center Göttingen
Alexander Flügel: University Medical Center Göttingen
Niklas Engels: University Medical Center Göttingen
Jürgen Wienands: University Medical Center Göttingen

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB’s nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions.

Date: 2024
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DOI: 10.1038/s41467-024-51166-3

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