Jonatan Ersching1, Alejo Efeyan1, Luka Mesin1, Johanne T Jacobsen2, Giulia Pasqual1, Brian C Grabiner1, David Dominguez-Sola3, David M Sabatini4, Gabriel D Victora5. 1. Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA. 2. Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA; Center for Immune Regulation, Oslo University Hospital, University of Oslo, N-0372 Oslo, Norway. 3. Department of Oncological Sciences, The Tisch Cancer Institute and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. 4. Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA; Howard Hughes Medical Institute, Cambridge, MA, 02142, USA. 5. Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA. Electronic address: victora@rockefeller.edu.
Abstract
During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell-cycle progression itself and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection.
During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the lpan class="Gene">ight zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell-cycle progression itself and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection.
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