Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

Abstract

In primary humoral responses, B-cell lymphoma 6 (Bcl6) is a master regulator of follicular helper T (T FH ) cell differentiation; however, its activation mechanisms and role in memory responses remain unclear. Here we demonstrate that survival of CXCR5 + T FH memory cells, and thus subsequent recall antibody response, require Bcl6 expression. Furthermore, we show that, upon rechallenge with soluble antigen Bcl6 in memory T FH cells is rapidly induced in a dendritic cell-independent manner and that peptide:class II complexes (pMHC) on cognate memory B cells significantly contribute to this induction. Given the previous evidence that antigen-specific B cells residing in the follicles acquire antigens within minutes of injection, our results suggest that memory B cells present antigens to the cognate T FH memory cells, thereby contributing to rapid Bcl6 reexpression and differentiation of the T FH memory cells during humoral memory responses.immunological memory | antibody production T he development of high-affinity B-cell memory is essential in most effective vaccines that are in use today. Because most protein antigens require T-cell help to induce B-cell responses, understanding the mechanisms by which memory T and B cells are generated and maintained, as well as how their swift activation is executed, is of fundamental importance for vaccine development.In primary immune responses, it is widely accepted that among several differentiated helper T-cell subsets follicular helper CD4 T cells (T FH cells) are the major subset to deliver help to B cells (1). T FH cells express CXC-chemokine receptor 5 (CXCR5), the chemokine receptor for the B-cell homing chemokine CXCL13. Surface expression of CXCR5 enables T FH cells to migrate into B-cell follicles, where they provide help to B cells to form germinal centers. In addition, T FH cells are needed for the crucial affinitymaturation process of B cells in germinal centers, whereby Agspecific B cells undergo repeated rounds of somatic hypermutation and positive selection by T FH cells to rapidly evolve high-affinity somatically mutated B-cell receptors. B-cell lymphoma 6 (Bcl6) has recently been identified as a T FH lineage regulator (2-4); it is highly expressed by T FH cells and is required for their development. According to the current view, during a primary response Bcl6 expression by T cells is induced by priming with dendritic cells (5-7) and ICOS is a key coreceptor molecule for induction of Bcl6 (5, Although the importance of Bcl6 and its expression kinetics in naïve T-cell differentiation have been well elucidated, its role and activation mechanisms in T FH memory cells still remain obscure. Hence, in this paper we first focus upon the roles of Bcl6, demonstrating its importance for maintenance of T FH memory cells. Then, we show that Bcl6 in memory T FH cells was rapidly induced upon rechallenge with soluble antigen and that this response was mainly mediated through antigen presentation by the cognate memory B cells. Given the good association between Bcl6 wi...

Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers

“…Either of these possibilities is intriguing, the latter because the maintenance of GC T cells by memory B cells has not been described in humans or mice previously. It has, however, been suggested that memory B cells are able to support lymph-node resident memory Tfh-like cells in mice, 56,57 raising the possibility that the Tfh cells identified in this study may represent a lymphoid reservoir of memory Tfh cells similar to those described in mice, 56 rather than a bona fide effector population. This seems unlikely, however, as CD57…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Bcl6 is essential for the induction of Tfh cell differentiation as the reciprocal repression of Bcl6 and BLIMP1 controls the development of Tfh vs. non‐Tfh CD4 + T helper cell populations (Johnston et al , 2009; Nurieva et al , 2009; Yu et al , 2009). At later stages, Bcl6 is required for stable Tfh effector commitment and the maintenance of memory Tfh cells (Liu et al , 2012; Ise et al , 2014). Still, the regulation of Bcl6 in the course of Tfh cell differentiation is incompletely understood.…”

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…All experiments used mice on a C57BL/6 background except where noted. BCL6 flox, IL-2 −/− , BLIMP-1 reporter, Foxp3 fusion protein DTR-GFP (FDG), Foxp3-Gfp eFox, and IL-21 reporter mice have already been described (45)(46)(47)(48)(49).…”