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

CD4 T 细胞中的 c-Myb 对于记忆抗体反应至关重要

• 批准号: 8820986
• 负责人: Timothy P. Bender
• 金额: $ 27.01万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820986
• 关键词: Adoptive Transfer; Affinity; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Autoantigens; Autoimmune Diseases; B-Lymphocytes; BLR1 gene; Bacillus anthracis; CD4 Positive T Lymphocytes; Cell physiology; Cells; Characteristics; Clinical; Data; Defect; Development; Disease; Effectiveness; Generations; Goals; HIV; Health; Homing; Human; Immunity; Immunization; Immunoglobulin-Secreting Cells; Immunologic Memory; Kinetics; Lymphoid; MYB gene; Memory; Memory B-Lymphocyte; Mouse Strains; Multiple Sclerosis; Mus; Pathogenesis; Peripheral; Plasmodium; Process; Property; Proto-Oncogene Proteins c-myb; Regulation; Role; Signal Transduction; Staging; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; TNFSF5 gene; Transgenic Organisms; Up-Regulation; Ursidae Family; Vaccination; Vaccine Design; Vaccines; base; cytokine; memory CD4 T lymphocyte; mouse model; neutralizing antibody; pathogen; prophylactic; research study; response; transcription factor

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.

描述（由申请方提供）：大多数疫苗通过诱导中和抗体赋予免疫力。成功的预防性疫苗接种诱导持久的抗体滴度和记忆B细胞池，其在遇到病原体时可以快速分泌高亲和力抗体。CD 4 T细胞通过控制记忆B细胞的形成和通过向活化的记忆B细胞提供快速T细胞帮助并促进其分化为抗体分泌细胞（ASC）而对于增强的二次抗体应答是必需的。众所周知，记忆B细胞最常在生发中心（GC）内形成，生发中心是依赖于辅助活性滤泡辅助性CD 4 T（Tfh）细胞的淋巴微环境。Tfh细胞可分为前Tfh细胞和GC Tfh细胞亚群。Pre-Tfh细胞在T-B滤泡边界处积累，其中与最近活化的B细胞的同源相互作用通过SAP和ICOS信号传导重新加强高Bcl-6表达，以驱动进一步分化为GC Tfh细胞。Bcl-6被认为是Tf分化的主要转录调节因子，并且表达与CD 4 T细胞上CXCR 5的上调相关。目前还不清楚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细胞从前体细胞的分化。记忆性CD 4 T细胞的GC归巢亚群也具有关键作用，其以细胞因子的形式有效地为最近活化的B细胞提供帮助，以类似于Tfh细胞的方式进行共刺激细胞-细胞接触。使用我们实验室开发的条件性小鼠模型，我们已经确定了CD 4 T细胞中c-MyB转录因子支持记忆B细胞应答的一个先前未知的功能。我们发现含有c-Myb缺陷的外周CD 4 T细胞的小鼠产生严重减少的回忆ASC反应，表明CD 4 T细胞中的c-Myb是免疫记忆的重要调节因子。连续转移实验表明，CD 4 T细胞中的c-MyB对于高亲和力记忆B细胞的发育至关重要。初步数据表明，具有MyB-/-CD 4 T细胞的小鼠在免疫后具有显著更少的携带记忆细胞特征性标志物的B细胞和CD 4 T细胞以及更少的Tfh细胞和GC B细胞。我们假设，c-MyB b是CD 4 T细胞中所需的，用于记忆B细胞的发育或用于支持与抗原（Ag）二次接触后记忆B细胞分化为ASC，或两者兼而有之。确定CD 4 T细胞中支持回忆抗体产生的c-Myb活性对疫苗设计具有重要意义。决定不同疫苗提供的保护的有效性和持久性的因素尚未完全了解，并且可能受到记忆细胞的定性或定量特性的影响。此外，C- MyB控制对自身抗原特异的记忆B细胞的抗体分泌（通过同源CD 4 T细胞的调节）可能会影响我们对自身免疫性疾病发病机制的理解。本提案的总体目标是了解CD 4 T细胞亚群中c-MyB的需求，这些亚群支持Ag特异性B细胞产生回忆抗体。

项目成果

Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes.

• DOI: 10.1042/bst20160169
• 发表时间: 2017-06-15
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Ziembik MA;Bender TP;Larner JM;Brautigan DL
• 通讯作者: Brautigan DL