Elucidating functional properties of memory B cells

描述（由申请人提供）：记忆B细胞分化为抗原呈递细胞和抗体产生细胞，对天然抗原和疫苗的长期免疫很重要，可能在自身免疫性疾病的临床表现中起关键作用。然而，记忆B细胞本身非常罕见，因此人们对其知之甚少。利用我们实验室开发的小鼠系统克服了研究B细胞记忆的重大障碍，我们使用Affymetrix微阵列比较了记忆B细胞与其原始前体之间的基因表达，并证实了几个概念上重要的家族在mRNA和蛋白质水平上的差异表达。基于这些基因在其他细胞类型中的已知功能，我们对它们的功能如何决定记忆B细胞的特性提出了假设。在此，我们提出验证以下假设：1)白血病抑制因子信号调节记忆B细胞自我更新和分化；2)记忆B细胞上的B7家族成员PD-L2在调节抗原刺激的二次反应中起核心作用。从长远来看，更好地了解记忆B细胞自我更新、分化和激活所需的事件将导致改进的疫苗接种策略。我的近期职业目标是，作为耶鲁大学皮肤病学助理教授，获得培训并开发解决这些B细胞记忆假说所需的系统。这项为期5年的指导计划将为许多长期项目和合作提供基础，并将促进我发展成为一名独立的研究者。相关性：对传染病形成“免疫记忆”的能力对健康和生存至关重要。这些拟议的研究将有助于阐明“记忆”的功能，以便更好地了解自然免疫和改进疫苗设计。

DESCRIPTION (provided by applicant): Memory B cells that differentiate into antigen presenting and antibody-producing cells are important for long-term immunity to natural antigens and vaccines and may play a key role mediating the clinical manifestations of autoimmune diseases. Memory B cells themselves, however, are typically rare and hence poorly understood. Using mouse systems developed in our laboratory that overcome significant barriers to the study of B cell memory, we compared gene expression between memory B cells and their naive precursors using Affymetrix microarrays and have confirmed the differential expression of several conceptually important families at the mRNA and protein level. Based on known functions of these genes in other cell types, we have developed hypotheses about how their functions determine properties of memory B cells. Here, we propose to test the hypotheses that: 1) leukemia inhibitory factor signaling regulates memory B cell self-renewal and differentiation and 2) the B7 family member PD-L2 on memory B cell plays a central role modulating the secondary response to antigenic stimulation. In the long-term, a better understanding of the events required for memory B cell self-renewal, differentiation and activation will lead to improved vaccination strategies. My immediate career goal, is to acquire the training and develop the systems required to address these hypotheses of B cell memory as an Assistant Professor of Dermatology at Yale. This proposed 5-year mentored program will provide the basis for many long-term projects and collaborations and will foster my development into an independent investigator. RELEVANCE: The ability to develop "immunological memory" to infectious diseases is critical for health and survival. These proposed studies will help elucidate how "memory" functions in order to better understand natural immunity and improve vaccine design.