Hypersensitivity to T_FH-secreted IL-21 licenses germinal center B cells with a fitness advantage

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Presentation Time: 05:30 PM - 05:45 PM
Abstract ID: 5333 - B

Presenting Author:
Coraline Mlynarczyk , Instructor of Cancer Immunology in Medicine at Weill Cornell Med.

Abstract:

BTG1 serves as a gatekeeper of fitness acquisition during the competitive selection of germinal center (GC) B cells. BTG1 mutation provides a fitness advantage to GC B cells, enabling them to outcompete their wild-type (WT) counterparts and yields aggressive B cell lymphomas (Mlynarczyk et al Science 2023).

We found that mutant BTG1 enables this supercompetitive effect by lowering the threshold of GC B cells to respond to positive selection signals from T follicular helper (T_FH cells), a limited and specialized population controlling GC B cell selection.

However, which T_FH cell signals are hijacked by BTG1 mutant cells and how downstream signaling is rewired to sustain superior fitness remain unknown.

Our data show that 1) transcriptional programs induced by interleukin 21 (IL-21, a T_FH cell-secreted cytokine) represent the major signaling pathway upregulated in BTG1 mutant mouse GC B cells, lymphoma patient samples and cell lines, 2) Btg1 mutant GC B cells contain a higher fraction of T_FH-selected cells expressing high IL-21 receptor levels, 3) are hypersensitive to IL-21 for downstream signaling activation and 4) outcompete WT cells in an IL-21-dose dependent manner, below a critical IL-21 threshold.

Our data points to hypersensitivity of GC B cells to T_FH-secreted IL-21 as a mechanism of competitive fitness gain under limiting IL-21 levels and suggests that signaling activation downstream of IL-21 receptor represents a dependency of BTG1 mutant B cell lymphomas.