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Contact

TEL: 06-6879-4457
Email: kurosaki@ifrec.osaka-u.ac.jp
Address: 9Fl. Integrated Life Science Building, Osaka University 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

Outline of Research

Kurosaki's lab on FY2013 Annual Report

Introduction

B cells play an essential role in the regulation of immune responses. Upon first encountering their cognate antigens, B cells exert multiple functions including antibody production, antigen-presentation, and induction of T cell differentiation. In addition to protective roles against pathogens, B cells also have regulatory roles, e.g. serving as negative regulators as autoimmunity by secreting anti-inflammatory cytokines such as IL-10 and TGF-. Our laboratory has now focused on deciphering when and where B cells produce IL-10, thereby dampening T-cell dependent inflammation. When B cells recognize the same antigen the second time, memory antibody responses can be induced by T cell help. These are typically seen in the response to T-cell-dependent antigens and are characterized by the rapid production of high-titers of high-affinity antigen-specific antibody. Based upon our previous evidence that memory B cell responses require T cells help, we are now characterizing how memory T cells are generated and contribute to robust memory antibody responses.

B cell role for immune suppression

Calcium signaling is thought to be critical for multiple B cell function; however, supportive in vivo evidence has been lacking. Thus, our discovery that Stim1 and Stim2 proteins are required in BCR-medicated calcium mobilization, has allowed us to approach this question by taking a genetic approach. We generated mice with B cell-specific deletions of both Stim1 and Stim2 and found that, although both molecules are critically required for in vitro proliferation, they were dispensable for B cell development and antibody responses in vivo. However, the ablation of Stim1 and Stim2 in B cells caused defects in NFAT activation, B cell intrinsic IL-10 production, and suppression of an EAE model of autoimmune diseases. Furthermore, we demonstrated that plasmablasts, but not B cells, indeed secret IL-10, which in turn acts on dendritic cells (DC) cells, thereby dampening T cell-mediated inflammation.

fig01

Figure 1: The model of regulatory function of plasmablasts
Plasmablasts are generated through the interactions between B cells and CD4+ T cells.
The plasmablast-derived IL-10 inhibits dendritic cell functions and thereby suppresses the generation of effector T cells such as Th1 and Th17 cells.

Interaction between memory T and B cells in humoral recall responses

In primary immune responses, it is widely accepted that among several differentiated helper T cell subsets, follicular helper CD4 T cells (TFH cells) are the major subset to deliver help to B cells. As a TFH lineage regulator, a transcription factor, Bcl6, has recently been identified; it is highly expressed by TFH 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 and ICOS is a key co-receptor molecule for induction of Bcl6. The initial Bcl6 induction and subsequent cXCR5 expression allow CD4 T cells to migrate toward the T-B border, where TFH cells interact with antigen-specific B cells. According to this model, cognate B cells are not required for the induction of Bcl6, but support the expansion of TFH cells. Although the importance of Bcl6 and its expression kinetics in naïve T cell differentiation have been well elucidated, its role and activation mechanisms in TFH memory cells still remain obscure. We demonstrated its importance for maintenance and activation of TFH memory cells. Indeed, Bcl6 in memory TFH cells is rapidly induced upon re-challenge by soluble antigen and this response is mainly mediated through antigen-presentation by the memory B cells. Thus, memory B cells are the primary APCs to induce the rapid differentiation of memory TFH cells toward effectors, further accelerating memory B cells responses during recall.