TFEB Activation Hallmarks Antigenic Experience of B Lymphocytes and Directs Germinal Center Fate Decisions

Authors

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
Jürgen Wienands

Publication Date

8-14-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-51166-3

PMID

39138218

PMCID

PMC11322606

PubMedCentral® Posted Date

8-14-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Germinal Center, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, B-Lymphocytes, Mice, Apoptosis, CD40 Antigens, Receptors, Antigen, B-Cell, Mice, Inbred C57BL, Lymphocyte Activation, Cell Differentiation, Signal Transduction, Antigen Presentation, B cells, B-cell receptor, Signal transduction, Gene regulation in immune cells, Immune cell death

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.