Germinal Center B Cell and T Follicular Helper Cell Development Initiates in the Interfollicular Zone

Abstract

Summary We identify the interfollicular (IF) zone as the site where germinal center B cell and T follicular helper (Tfh) cell differentiation initiates. For the first two days post-immunization, antigen-specific T and B cells remained confined within the IF zone, formed long-lived interactions, and upregulated the transcriptional repressor Bcl6. T cells also acquired the Tfh cell markers CXCR5, PD-1 and GL7. Responding B and T cells migrated to the follicle interior directly from the IF zone, T cell immigration preceding B cells by one day. Notably, in the absence of cognate B cells, Tfh cells still formed and migrated to the follicle. However, without such B cells, PD-1, ICOS and GL7 were no longer expressed on follicular Bcl6hi T cells that nevertheless persisted in the follicle. Thus, Ag-specific B cells are required for the maintenance of the PD-1hi ICOShi GL7hi Tfh cell phenotype within the follicle, but not for their initial differentiation in the IF zone.

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

“…In addition, we found that TLR9 signaling in DCs and/or B cells had a number of qualitative effects on the T FH cell population, including up-regulation of ICOS; down-regulation of PD-1; and alterations in their cytokine profiles, namely, increased IL-21 and IFN-γ and reduced IL-4. These results add to the emerging view that full T FH cell maturation occurs via two checkpoints: (i) Initial activation of naive T cells by DCs induces some of them to become T FH cells, and (ii) subsequent interaction with antigen-presenting B cells induces T FH cells to acquire a full GC T FH cell phenotype, allowing them to enter GCs and contribute to selection (38,(47)(48)(49)(50). Our data show that both steps are modulated by TLR9 signaling in the antigen-presenting cell to enhance the number and/or properties of T FH cells.…”

A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA

“…T FH are typically identified by co-expression of CXCR5 together with other markers including ICOS, PD-1, BCL-6 (Breitfeld et al, 2000;Kim et al, 2001) (Choi et al, 2011;Fazilleau et al, 2009;Kerfoot et al, 2011;King, 2009;Laurent et al, 2010). A number of cytokines, particularly IL-21, are produced by T FH , and are considered to have a major role in T FH differentiation and function on B cell antibody response (King, 2009).…”

Mechanisms of action of BCL6 during germinal center B cell development

“…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.…”