| Autor: |
Münchhalfen, Matthias, Görg, Richard, Haberl, Michael, Löber, Jens, Willenbrink, Jakob, Schwarzt, Laura, Höltermann, Charlotte, Ickes, Christian, Hammermann, Leonard, Kus, Jan, Chapuy, Björn, Ballabio, Andrea, Reichardt, Sybille D., Flügel, Alexander, Engels, Niklas, Wienands, Jürgen |
| Předmět: |
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| Zdroj: |
Nature Communications; 8/14/2024, Vol. 15 Issue 1, p1-21, 21p |
| Abstrakt: |
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. B cell receptor activation leads to contrary outcomes in the absence and presence of co-stimulation. Here, the authors show transcription factor EB acts as a B cell receptor-controlled rheostat that balances activation-induced cell death with co-stimulatory rescue signals, collectively reprograming antigen-primed germinal center B cells for fate decisions. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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