Laboratory for Lymphocyte Differentiation

Current research

Memory humoral responses are typically more rapid, have a greater magnitude, and consist of antibodies of higher affinity than in the primary response. Our laboratory has now focused on clarifying the functional characterization of memory B cells and memory T cells and on revealing the mechanisms underlying the robustness of memory antibody responses. Our findings will provide us with a mechanistic basis for developing vaccines, for example influenza vaccine, to maximize their effector immune responses.

 

Characterization of memory T_FH cells

CD4 T cells are critical for memory B cell generation and their subsequent activation. Previously, we demonstrated that CXCR5⁺ CD4 T cells reside nearby the IgG1 memory B cells in the follicles (Aiba et al, PNAS, 2010) at the memory phase. Based on these results, we hypothesized that a fraction of antigen-specific effector T cells, especially T_FH cells, survives over the contraction phase and becomes memory CXCR5⁺ T_FH cells which participate in recall antibody responses. Thus, we first, by using the transgenic TCR model, verified our idea. In addition, our data suggest that memory B cells function as APCs to rapidly induce Bcl6 in T_FH memory T cells, thereby contributing to robust humoral memory responses.

 

Regulation of Bach2 during immune responses

We previously proposed that reorganization of transcription factors (for instance, repression of Bach2) takes place during generation of IgG1 type memory B cells after primary antigen exposure, and is critical for rapid responsiveness of IgG1 memory B cells (BCR-extrinsic model) (Kometani et al, Immunity, 2013). To directly test this model, we have established mice in which Bach2 could be overexpressed or knocked out in an inducible manner. When Bach2 was overexpressed just before secondary responses, IgG1 type memory B cells became skewed toward generation of GC B cells rather than differentiating into plasma cells. Conversely, deletion of Bach2 promoted preferential differentiation into plasma cells. These results clearly suggest that the expression level of Bach2 is involved in the functions of memory B cells.

 

Figure: Bcl6 activation mechanisms in naive versus memory T cells

During primary immune responses, naïve T cells are primed with antigen-presenting dendritic cells and differentiate into effector cells. Some of the activated T cells up-regulate Bcl6 expression. The Bcl6⁺ cells express the CXCR5 chemokine receptor , which leads them to the T-B border, where cognate interactions between Bcl6⁺ T cells and antigen-specific B cells occur. In contrast to primary responses, memory T_FH cells are activated directly by antigen-presenting memory B cells and quickly gain high levels of Bcl6 expression and re-differentiate into effector T_FH cells, which contribute to activation of memory B cells.