Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

Abstract

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.DOI: http://dx.doi.org/10.7554/eLife.19552.001

BAFF, IL‐4 and IL‐21 separably program germinal center‐like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L‐activated B cells in vitro

“…From these findings it is of interest to consider when and where activated B cells may encounter these cytokines. In lymphoid immune responses, B cells migrate proximal to cognate helper T cells in the interfollicular zones in the first 2–3 days of the response . Differentiation, with associated migration to extrafollicular regions as plasmablasts or coalescence on follicular dendritic cell networks within follicles as GC, occurs subsequently, between days 3 and 7 .…”

Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches

“…8 Within primary follicles FDCs are a key source of CXCL13, a chemokine that is requisite for the correct organization of GCs into compartmentalized DZ and LZs. [20][21][22][23][24][25][26] At the peak of the response, Tfh can be distinguished from other cell subsets by a high level of expression of the molecules PD-1, ICOS, and the chemokine receptor CXCR5. [11][12][13][14][15] FDCs can serve as long-term depots of undegraded Ag, 11,13,[15][16][17] and for this reason they have classically been considered an important site of antigen presentation to B cells.…”

“…92,151 Thus, IRF4 is required for both ASC and GC development, although ASCassociated genes are promoted when IRF4 is at sustained or high levels of expression. [20][21][22][23][24][25][26] The combined expression of IL-4 and IL-21 is unique to Tfh cells, however, all Th-cell populations defined to date are thought to express CD40L, and very early in an immune response. [20][21][22][23][24][25][26] The combined expression of IL-4 and IL-21 is unique to Tfh cells, however, all Th-cell populations defined to date are thought to express CD40L, and very early in an immune response.…”

“…26 Bcl6 controls GC B cell differentiation by regulating cell cycle genes, repressing terminal differentiation factors, and suppressing some signaling pathways, including some aspects of BCR signaling. 26 Bcl6 controls GC B cell differentiation by regulating cell cycle genes, repressing terminal differentiation factors, and suppressing some signaling pathways, including some aspects of BCR signaling.…”

“…26 Interestingly, the shift from the immature pre-GC B cell state to the more mature Bcl6hi state involves both transcriptional and post-transcriptional regulation, 26 the latter a form of regulation that can be mediated by micro-RNAs. 26,165 Based on these results, a model of initial GC B cell differentiation has been proposed to be a multistaged process completed by a transient diminution in the receipt of T-cell help within its immediate microenvironment ( Figure 2). However, when CD40 agonism is prolonged or additional soluble antigen is introduced, GC precursors are instead expanded and shunted away from the intrafollicular GC pathway.…”