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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.
Highlights
Germinal centers (GCs) are specialized structures that form within B cell follicles in response to immunization or pathogen exposure
The results presented here shed light on a longstanding conundrum; how can CD40 signaling be required for B cell commitment to the GC lineage while inhibiting its formation? We find that GC B cell differentiation is a two-stage process; (1) a T-cell contact and CD40-dependent phase that generates RelB+ IRF4+ BCL6int GC precursors and (2) a phase immediately following that is prevented by further CD40 signaling but needed to complete their transition to BCL6hi GC B cells
The immediate precursors to GC B cells are poised at an incomplete state of differentiation that can be diverted by extending T cell help or by introducing anti-CD40
Summary
Germinal centers (GCs) are specialized structures that form within B cell follicles in response to immunization or pathogen exposure. Within defined anatomical niches of mature GCs, antigen specific GC B cells intermittently engage cognate T follicular helper cells (Tfh). After antigen binding and B cell receptor (BCR) signaling, activated follicular B cells migrate to the T/B border and interfollicular (IF) regions. At the periphery of follicles, responding B and T cells engage, separate and re-form contacts with new cognate partners over the course of several days (Kerfoot et al, 2011). Initial B cell commitment to the GC lineage and divergence from the short-term antibody secreting cell (ASC) path occurs during this time period (Kerfoot et al, 2011). Tfh migration into the follicle interior precedes that of GC committed B cells (Kerfoot et al, 2011)
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