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抗体是免疫系统重要的组成部分，发挥重要的免疫学功能。抗体由B细胞或其终末分化细胞浆细胞产生，然而, B细胞的分化和抗体的产生均需要T细胞的辅助。目前，已经证明滤泡辅助性T细胞（T follicular helper cells，TFH）是主要的辅助B细胞的T细胞亚群。我们研究组致力于研究与抗体生成密切相关的TFH细胞以及成熟B细胞的分化及相关的机制。具体研究方向与内容如下：
（1）TFH细胞分化的转录调节机制
TFH细胞是新发现的CD4+辅助性T细胞亚群，高表达CXCR5、PD-1、ICOS等表面分子，Bcl-6是其关键的转录因子。近年来，TFH细胞领域的研究取得很大的进展，但是人们对TFH细胞的认识仍然很不清楚，尚有许多相关问题亟待解决，比如TFH细胞分化机制、体外分化体系、临床应用等。近期，我们发现Foxp1是TFH细胞分化过程关键的负调节因子，并初步揭示了其调节机制，如Foxp1负调节ICOS的信号，以及抑制细胞因子IL-21的表达等 (Nature Immunology. 2014;15(7):667-75)，但是确切的机制仍需进一步的探讨。我们将在已有基础上，进一步探讨关键的信号通路和转录因子在TFH细胞分化过程中的作用，并开展TFH细胞在疫苗研究中的应用。
（2）成熟B细胞分化的转录调节研究
抗原特异性免疫反应中，B细胞的分化是与TFH细胞密切相关的一个复杂过程，直接影响抗体的生成。B细胞分化的每一阶段都有不同的信号网络调节B细胞增殖、存活和分化，每一步异常的分化都有可能导致肿瘤的发生。我们发现Foxp1除了在T细胞中发挥重要的功能外，对成熟B的分化过程中也具有重要的作用。此项课题中，我们将研究Foxp1在成熟B细胞的功能以及内在的机制，并探讨Foxp1在弥漫性大B细胞淋巴瘤（DLBCL, Diffuse large B-cell lymphoma的作用和机理。
Research direction
Production of high affinity and long-lived antibodies by immune cells is critically essential for protection against infectious diseases, and it is also the foundation of most effective vaccines. Our research aims to understand transcriptional regulation in the development and function of Follicular Helper T (TFH) cells and B cells, two key components of humoral immunity. Knowledge obtained in our studies will facilitate new vaccine development, meanwhile offering new strategies for the treatment of infectious diseases such as HIV and influenza.
1. Transcriptional regulation in TFH cells development.
Follicular helper T cells (TFH cells) are a specialized CD4+ T cell subset that provides B cell help for germinal center formation. TFH cells are characterized by the expression of surface molecules that facilitate functional interactions with B cells such as the chemokine receptor CXCR5, ICOS and PD-1. The transcription factor Bcl-6 is a central regulator of TFH cell differentiation, and the cytokine interleukin 21 is a key cytokine for both TFH and germinal center B cell differentiation. Although the essential function of TFH for germinal center formation has been elucidated, how TFH cells differentiate from CD4+ effector T cells remains unclear. We are interested in the key signaling pathways and transcription factors involved in T differentiation and functions.
2. Transcriptional regulation of mature B cell differentiation.
Mature B cell differentiation is also a complex process. After encountering antigen and receiving cognate T cell help, mature B cells form germinal centers in the follicles, where B cells undergo clonal expansion, selection, and differentiation into either memory B cells or plasma cells. At each differentiation step, distinct regulatory networks are engaged to regulate the B cell proliferation, survival and differentiation. Perturbations in B cell differentiation give rise to certain types of lymphoma. Here, we aim to identify novel stage-specific transcriptional networks that regulate mature B cell differentiation, with a particular focus on the molecules that are known to be associated with the pathogenesis of B lymphomas. Built on our past work, our current study will focus on the roles of Foxp1 in mature B cells differentiation and human B cell lymphomas.