{Reference Type}: Journal Article
{Title}: TFEB activation hallmarks antigenic experience of B lymphocytes and directs germinal center fate decisions.
{Author}: Münchhalfen M;Görg R;Haberl M;Löber J;Willenbrink J;Schwarzt L;Höltermann C;Ickes C;Hammermann L;Kus J;Chapuy B;Ballabio A;Reichardt SD;Flügel A;Engels N;Wienands J;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Aug 14
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-51166-3
{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.