c-Myb in CD4 T cells is crucial for recall antibody responses

描述（由申请人提供）：大多数疫苗通过诱导中和抗体赋予免疫。成功的预防性疫苗接种诱导持久的抗体滴度和记忆B细胞库，可以在遇到病原体时迅速分泌高亲和力抗体。CD4 T细胞通过控制记忆B细胞的形成和提供快速T细胞帮助激活记忆B细胞并促进其分化为抗体分泌细胞（ASCs），对增强二抗反应至关重要。记忆B细胞通常在生发中心（GCs）内形成，这是一种依赖于辅助活性的淋巴微环境，滤泡辅助CD4 T （Tfh）细胞。Tfh细胞可分为前置Tfh细胞亚群和GC Tfh细胞亚群。前Tfh细胞聚集在T-B滤泡边界，在那里，与最近激活的B细胞的同源相互作用通过SAP和ICOS信号增强了Bcl-6的高表达，从而进一步分化为GC Tfh细胞。Bcl-6被认为是Tf分化的主要转录调控因子，其表达与CD4 T细胞上CXCR5的上调相关。目前尚不清楚Tfh细胞（无论是作为前Tfh细胞还是GC Tfh细胞）如何调节记忆B细胞与前体的分化。记忆CD4 T细胞的gc归巢亚群也起着至关重要的作用，它以细胞因子的形式有效地为最近激活的B细胞提供帮助，并以类似于Tfh细胞的方式共同刺激细胞-细胞接触。使用我们实验室开发的条件小鼠模型，我们已经确定了CD4 T细胞中c-Myb转录因子先前未知的功能，该功能支持记忆B细胞反应。我们发现含有c-Myb缺陷的外周CD4 T细胞的小鼠产生严重减少的回忆ASC反应，这表明CD4 T细胞中的c-Myb是免疫记忆的重要调节因子。过继性转移实验表明，CD4 T细胞中的c-Myb对高亲和记忆B细胞的发育至关重要。初步数据表明，Myb-/- CD4 T细胞小鼠免疫后具有记忆细胞特征的B细胞和CD4 T细胞数量显著减少，Tfh细胞和GC B细胞数量也明显减少。我们假设c-Myb在CD4 T细胞中是必需的，用于记忆B细胞的发育，或在与抗原（Ag）二次相遇后支持ASCs从记忆B细胞分化，或两者兼有。确定支持召回抗体产生的CD4 T细胞中c-Myb的活性对疫苗设计具有重要意义。决定不同疫苗提供保护的有效性和持久性的因素尚未完全了解，并可能受到记忆细胞的定性或定量特性的影响。此外，c-的势

DESCRIPTION (provided by applicant): Most vaccines confer immunity through induction of neutralizing antibody. Successful prophylactic vaccination induces durable antibody titers and a memory B cell pool that can rapidly secrete high-affinity antibody upon encounter with pathogens. CD4 T cells are essential for enhanced secondary antibody responses both by controlling the formation of memory B cells and by providing rapid T cell help to activated memory B cells and promote their differentiation into antibody-secreting cells (ASCs). It is well-established that memory B cells are most often formed within germinal centers (GCs), a lymphoid microenvironment that is reliant on the helper activity follicular helper CD4 T (Tfh) cells. Tfh cells can be classified into pre-Tfh cell and GC Tfh cell subsets. Pre-Tfh cells accumulate at the T-B follicular border where cognate interaction with recently-activated B cells re-enforces high Bcl-6 expression through SAP and ICOS signaling to drive further differentiation to GC Tfh cells. Bcl-6 is considered to be a master transcriptional regulator of Tf differentiation and expression correlates with up-regulation of CXCR5 on CD4 T cells. It is not understood how Tfh cells, either as pre-Tfh or GC Tfh cells, regulate the differentiation of memory B cells from precursors. There is also a crucial role for a GC-homing subset of memory CD4 T cells that efficiently provide help to recently-activated B cells in the form of cytokines an co-stimulatory cell-cell contact in a manner similar to Tfh cells. Using a conditional mouse model developed in our lab we have identified a previously unknown function for the c-Myb transcription factor in CD4 T cells that support memory B cell responses. We find mice that contain c-Myb-deficient peripheral CD4 T cells produce severely diminished recall ASC responses, suggesting that c-Myb in CD4 T cells is an important regulator of immunological memory. Adoptive transfer experiments demonstrate that c-Myb in CD4 T cells is crucial for the development of high affinity memory B cells. Preliminary data demonstrate that mice with Myb-/- CD4 T cells have substantially fewer B cells and CD4 T cells that bear markers characteristic of memory cells as well as fewer Tfh cells and GC B cells after immunization. We hypothesize that c-Myb is required in CD4 T cells for development of memory B cells or for supporting differentiation of ASCs from memory B cells after secondary encounter with antigen (Ag), or for both. Defining the activity of c-Myb in CD4 T cells that support recall antibody production has significant implications for vaccine design. The factors that determine the effectiveness and durability of protection afforded by different vaccines are not fully understood and could be influenced by qualitative or quantitative properties of memory cells. Moreover, the potential of c- Myb to control antibody secretion from memory B cells that are specific for autoantigens (through regulation by cognate CD4 T cells) could have impact on our understanding of the pathogenesis of autoimmune disease. The overall goal of this proposal is to understand the requirements for c-Myb in CD4 T cell subsets that support generation of recall antibody production from Ag-specific B cells.