Bcl6 Protein Expression Shapes Pre-Germinal Center B Cell Dynamics and Follicular Helper T Cell Heterogeneity

Abstract

The transcription factor Bcl6 is essential for the development of germinal center (GC) B cells and follicular helper T (Tfh) cells. However, little is known about in vivo dynamics of Bcl6 protein expression during and after development of these cells. By using a Bcl6 reporter mouse strain, we found that antigen-engaged B cells upregulated Bcl6 before clustering in GCs. Two-photon microscopic analysis indicated that Bcl6 upregulation in pre-GC B cells contributed to sustaining their interactions with helper T cells and was required for their entry to GC clusters. Our data also suggested that Tfh cells gradually downmodulated Bcl6 protein over weeks after development. The Bcl6-low Tfh cells rapidly terminated proliferation and upregulated IL-7 receptor. These results clarify the role of Bcl6 in pre-GC B cell dynamics and highlight the modulation of Bcl6 expression in Tfh cells that persist in the late phase of the antibody response.

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…This is in accordance with the fact that T FH cells may downregulate Bcl6 over weeks after antigenic challenge. 56 Recently, Morita et al 52 shed light on the relationship between T FHC (CD4 1 CXCR5 1 ) and T FH cells and convincingly demonstrated that T FHC cells share functional, and to some extent phenotypic, properties of T FH cells present in the lymphoid organs of humans and mice, and constitute a subset of circulating pool of memory T FH cells. They found T FHC cells to be potent at providing help for B-cell responses, such as production of plasmablasts and promotion of class switching through IL-21.…”

Mechanisms of action of BCL6 during germinal center B cell development

“…BCL6 up-regulation appears to be important for pre-GC B cell to form sustained interaction with cognate Tfh cells and move towards the center of the follicle. BCL6 seems to drive pre-GC B cell migration at least in part through directly inhibiting the trafficking factors Sphingosine 1-phosphate receptor 1 (S1PR1) and GPR183, which encodes G protein-coupled receptor 183 [21,31]. These new findings point to multifaceted biological functions of BCL6 in the GC response.…”

“…The first step towards GC formation is activation of naïve B cells by exogenous T-cell dependent antigen in the follicles of peripheral lymphoid tissues. Next, antigen-engaged B-cells migrate to the border between the follicles and the T cell zone or interfollicular zones, where they undergo proliferation and interact with cognate Tfh cells within 1-3 days after stimulation [18][19][20][21]. B-cells can then differentiate into extrafollicular plasma cells and leave the follicle to generate low-affinity antibodies, or alternatively can enter the GC pathway [22].…”

“…These early GC precursor B cells (i.e. pre-GC B cells) begin to up-regulate expression of BCL6 protein and move toward the center of lymphoid follicles [20,21]. BCL6 up-regulation in pre-GC B cells contributes to their sustained interactions with Tfh cells and is required for their further differentiation in the lymphoid follicles.…”

“…Recent studies using Bcl6-reporter mice and high-resolution intravital cellular imaging have established a critical role for BCL6 in pre-GC events [20,21]. BCL6 protein is first detected in the interfollicular zone in a small subset of activated antigen-engaged B cells that have been successfully engaged by Tfh cells.…”