Elucidating functional properties of memory B cells

描述(由申请人提供)：记忆B细胞分化为抗原提呈细胞和抗体产生细胞，对于对天然抗原和疫苗的长期免疫非常重要，并可能在自身免疫性疾病的临床表现中发挥关键作用。然而，记忆B细胞本身通常是稀有的，因此人们对其知之甚少。利用我们实验室开发的克服B细胞记忆研究的重大障碍的小鼠系统，我们使用Affymetrix微阵列比较了记忆B细胞及其原始前体细胞的基因表达，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，我们提出了关于它们的功能如何决定记忆B细胞特性的假设。在此，我们提出了如下假设：1)白血病抑制因子信号转导调节记忆B细胞的自我更新和分化；2)记忆B细胞上的B7家族成员PD-L2在调节对抗原刺激的次级反应中起核心作用。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疫苗接种策略。作为耶鲁大学皮肤病学的助理教授，我的直接职业目标是获得培训并开发必要的系统，以解决这些关于B细胞记忆的假设。这个拟议的5年指导计划将为许多长期项目和合作提供基础，并将把我培养成一名独立的调查员。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”是如何发挥作用的，以便更好地了解自然免疫并改进疫苗设计。

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.