Abstract
Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites.
Original language | English |
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Article number | 20191043 |
Number of pages | 19 |
Journal | Journal of Experimental Medicine |
Volume | 217 |
Issue number | 3 |
Early online date | 29 Dec 2019 |
DOIs | |
Publication status | Published - 2 Mar 2020 |
Funding
We thank Dr. Gabriel Victora for valuable comments and discussions. We thank Dr. Hadas Keren-Shaul from the Sandbox unit in the Life Science Core Facility of the Weizmann Institute of Science for guidance and critical advice regarding sequencing. Z. Shulman is supported by European Research Council grant no. 677713, the Israel Science Foundation (2759/19), and the German Israeli Foundation for Scientific Research and Development (2506). Z. Shulman is a member of the European Molecular Biology Organization Young Investigator Program, and also supported by the Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, and Rising Tide Foundation, Morris Kahn Institute for Human Immunology, and grants from the Benoziyo Endowment Fund for the Advancement of Science, Sir Charles Clore Research Prize, Comisaroff Family Trust, Irma and Jacques Ber-Lehmsdorf Foundation, Gerald O. Mann Charitable Foundation, and David M. Polen Charitable Trust. Author contributions: N. Davidzohn designed and conducted the experiments, performed data analysis, and wrote the manuscript; A. Biram designed and performed experiments; L. Stoler-Barak generated transgenic mice; A. Grenov designed and performed the Kras experiments; B. Dassa performed and interpreted computational analyses; Z. Shulman designed experiments, supervised the study, and wrote the manuscript.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology