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Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase.

Immunity | Jun 20, 2017

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.

Pubmed ID: 28636954 RIS Download

Mesh terms: Animals | Antibody Affinity | B-Lymphocytes | Cell Cycle | Cell Proliferation | Cells, Cultured | Clonal Selection, Antigen-Mediated | Cytokines | Germinal Center | Mechanistic Target of Rapamycin Complex 1 | Mice | Mice, Inbred C57BL | Mice, Transgenic | Multiprotein Complexes | Receptors, Antigen, B-Cell | Sirolimus | Somatic Hypermutation, Immunoglobulin | T-Lymphocytes, Helper-Inducer | TOR Serine-Threonine Kinases

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Associated grants

  • Agency: NIAID NIH HHS, Id: R01 AI047389
  • Agency: NCI NIH HHS, Id: R01 CA103866
  • Agency: NIH HHS, Id: DP5 OD012146
  • Agency: NCI NIH HHS, Id: R00 CA151827
  • Agency: NIAID NIH HHS, Id: R37 AI047389
  • Agency: NIAID NIH HHS, Id: R01 AI119006
  • Agency: Howard Hughes Medical Institute, Id:

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