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

Abstract

SUMMARY 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.

Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection

“…Additionally, blocking IL-15R signals by administration of anti-IL2Rβ (CD122) antibodies in vivo did not affect IEL re-positioning or dynamics post infection (Figure S5E–G). To address whether modulation of mTOR in hematopoietic cells, rather than in the non-hematopoietic or epithelial compartment, was sufficient to induce changes in IELs post infection, we used irradiated wild type or rapamycin-insensitive Mtor F2108L mice (Ersching et al, 2017) as hosts for TCRγδ GFP bone marrow. Rapamycin treatment suppressed infection-induced IEL flossing in both wild type and Mtor F2108L hosts, suggesting that mTOR inhibition in T cells is sufficient to prevent changes in IEL dynamics upon infection (Figure S5H; Figure 5D).…”

New Methods To Analyze B Cell Immune Responses to Thymus-Dependent Antigen Sheep Red Blood Cells

“…To further demonstrate that our method can detect changes in SRBC-specific antibody levels in a biologically relevant setting, we injected SRBC-immunized mice with the mTORC1 inhibitor rapamycin. mTORC1 is a central regulator of B cell metabolism and protein synsthesis and blocking mTORC1 activity in immunized mice prevents clonal expansion of B cells and leads to decreased plasma cell generation (8, 9). Consistently, 7d after immunization with SRBC, mice treated with vehicle only showed significantly higher levels of SRBC-specific IgM as mice treated with rapamycin (Fig.…”

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…(Figures 3 and 4). 47 However, this is followed by the progressive extinction of mTORC1-constitutively active GC B cells, which feature a competitive disadvantage due, at least in part, to a failure to undergo affinity maturation. 47 However, this is followed by the progressive extinction of mTORC1-constitutively active GC B cells, which feature a competitive disadvantage due, at least in part, to a failure to undergo affinity maturation.…”