IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation

Stéphane Chevrier, Tobias Kratina, Dianne Emslie, David M. Tarlinton, Lynn M. Corcoran

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

Bcl6 (B-cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T-cell-dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B-cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B-cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B-cell receptor (BCR) signal, but that the T-cell-derived cytokines interleukin 4 (IL4) and IL21 counteract BCR-mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B-cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T-follicular helper cytokines on Bcl6 regulation.

Original languageEnglish
Pages (from-to)925-932
Number of pages8
JournalImmunology and Cell Biology
Volume95
Issue number10
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

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