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


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Abstract

SummaryDuring 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.Graphical AbstractHighlightsPositive selection of GC B cells triggers mTORC1 activation prior to clonal expansionmTORC1 is required for biomass accumulation but dispensable for cell-cycle progressionDeregulated mTORC1 promotes DZ phenotype and leads to loss of GC competitivenessRapamycin-resistant mouse strain is used for cell-intrinsic mTORC1 inhibitionDuring germinal center selection, signals from Tfh cells in the light zone dictate the extent of B cell proliferation in the dark zone. Ersching et al. (2017) show that Tfh help induces mTORC1 activation in light zone B cells, leading to cell growth that sustains the subsequent dark zone proliferative burst.

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