Regulation of humoral immunity by NKT cells

NKT细胞调节体液免疫

• 批准号: 8013498
• 负责人: Mark L Lang
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013498
• 关键词: Adoptive Transfer; Affect; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding; Bone Marrow; CD40 Ligand; Cell Survival; Cell physiology; Cells; Data; Development; Enhancing Antibodies; Family member; Future; Galactosylceramides; Generations; Glycolipids; Health; Humoral Immunities; Immune response; Immune system; Immunization; Interleukin-5; Label; Learning; Life; Longevity; Maintenance; Mediating; Memory B-Lymphocyte; Mus; Myeloid Cells; Plasma Cells; Procedures; Proteins; Regulation; Reporting; Research; Supporting Cell; TNF gene; TNFRSF5 gene; TNFSF5 gene; Testing; Time; Vaccines; Work; cytokine; design; improved; in vitro Assay; in vivo; neutralizing antibody; novel; novel vaccines; pathogen; plasma cell development; reconstitution; research study; response; vaccination strategy

DESCRIPTION (provided by applicant): Our most effective vaccines stimulate long-term neutralizing Ab responses by stimulating the immune system to maintain Ag-specific memory B cells and long-lived Ab-secreting plasma cells. In order to develop more effective Ab-stimulating vaccines in future, we need to improve our understanding of the mechanisms by which humoral immunity is induced and maintained. We reported that activation of CD1d- restricted NKT cells with the CD1d-binding glycolipid 1-Galactosylceramide (1-GC) at the time of immunization with a protein Ag resulted in enhanced Ab responses to that Ag. Since then we have observed that NKT cells enhance Ab recall responses following a secondary booster with Ag. We have also obtained data consistent with the hypothesis that the recall responses are a result of NKT cells enhancing memory B cell induction and plasma cell longevity. Despite this progress there are no current reports on the mechanisms by which NKT cells contribute to induction and maintenance of humoral immunity. Our preliminary data suggest that NKT cells utilize several mechanisms to induce and maintain an effective humoral immune response. These include (i) NKT-derived IL-5 which supports plasma cell induction (ii) NKT-expressed CD154 a ligand for CD40 expressed on B cells and perhaps important for the induction of primary Ab responses and memory B cells (iii) The TNF family member BAFF (B cell-activating factor) that promotes development and survival of plasma cells. In this proposal we will examine the mechanisms by which NKT cells impact humoral immune responses. Hypothesis and Aims: We will test the hypothesis that NKT cell-derived cytokines, CD154 and plasma cell survival factor BAFF contribute substantially to humoral immune responses by supporting the induction and maintenance of the memory B cell and long-lived plasma cell pool. In Specific Aim 1, we will assess the effects of CD1d-dependent NKT activation and NKT absence on humoral immune responses. In Specific Aim 2, we will determine how NKT-derived IL-5 and CD154 enhance humoral immune responses. In Specific Aim 3, we will determine if NKT-derived BAFF influences the induction of long-lived Ag-specific plasma cells. We will elucidate the mechanisms by which NKT cells support and enhance the induction and maintenance of humoral immune responses, thus integrating two previously diverse fields of research and substantially contributing to both. Our findings will be valuable for understanding humoral immunity and may contribute to the design of novel vaccination strategies that incorporate NKT activation. PUBLIC HEALTH RELEVANCE: Most successful vaccines stimulate long-lived humoral immune responses mediated by protective antibody. Despite remarkable progress in understanding the mechanisms by which humoral immunity is induced and sustained, there is much to learn. This is of particular importance if we are to develop novel vaccines in the future against remaining pathogens for which there is no vaccine. We have discovered that activation of NKT cells enhances primary and recall antibody responses. Our data indicate that this is due to increasing the generation of memory B cells, the precursor of antibody-secreting plasma cells and by increasing the persistence of plasma cells. Our project will assess the impact of NKT cells on memory B cell and plasma cell induction and maintenance. We will then conduct mechanistic studies to understand how NKT cells achieve their effects on memory B cells and plasma cells. Our work will advance the understanding of the mechanisms by which NKT cells affect humoral immune responses and may highlight new opportunities to develop novel vaccine strategies.

描述（由申请人提供）：我们最有效的疫苗通过刺激免疫系统维持Ag特异性记忆B细胞和长期分泌AB的浆细胞来刺激长期中和AB反应。为了在将来开发更有效的AB刺激疫苗，我们需要提高对诱导和维持体液免疫的机制的理解。我们报道说，用CD1D结合糖胶质1-半乳糖基酰胺（1-GC）在免疫接种时用蛋白质AG激活CD1D限制的NKT细胞，从而激活AB对该Ag的AB反应增强。从那时起，我们观察到NKT细胞在使用Ag的次级增强后增强了AB召回反应。我们还获得了与召回响应是NKT细胞增强记忆B细胞诱导和浆细胞寿命的结果的假设一致的数据。尽管取得了这种进展，但目前尚无关于NKT细胞有助于诱导和维持体液免疫力的机制的报告。我们的初步数据表明，NKT细胞利用几种机制诱导和维持有效的体液免疫反应。其中包括（i）支持浆细胞诱导的NKT衍生的IL-5（II）NKT表达的CD154 CD40的配体，用于B细胞表达的CD40，可能对诱导主要的AB反应和记忆B细胞（III）TNF家族成员BAFF（B细胞激活因子）（B细胞激活因子）（B细胞激活因子）促进发育和生存的生存。在此提案中，我们将研究NKT细胞影响体液免疫反应的机制。假设和目的：我们将检验以下假设：NKT细胞衍生的细胞因子CD154和浆细胞存活因子BAFF通过支持记忆B细胞的诱导和维护和长期寿命的plasma细胞池，从而有助于体液免疫反应。在特定的目标1中，我们将评估CD1D依赖性NKT激活和NKT缺失对体液免疫反应的影响。在特定目标2中，我们将确定NKT衍生的IL-5和CD154如何增强体液免疫反应。在特定的目标3中，我们将确定NKT衍生的BAFF是否会影响长寿特异性浆细胞的诱导。我们将阐明NKT细胞支持并增强体液免疫反应的诱导和维持的机制，从而整合了两个先前多样化的研究领域并实质性地促成两者。我们的发现对于理解体液免疫将很有价值，并可能有助于设计纳入NKT激活的新型疫苗接种策略。公共卫生相关性：大多数成功的疫苗刺激了保护性抗体介导的长寿命的体液免疫反应。尽管在理解诱导和维持体液免疫的机制方面取得了显着进展，但仍有很多学习。如果我们将来要开发新的疫苗，以防止没有疫苗的剩余病原体开发新型疫苗，这一点尤为重要。我们发现NKT细胞的激活增强了原发性和回忆抗体反应。我们的数据表明，这是由于增加了记忆B细胞的产生，这是分泌浆细胞的前体以及增加浆细胞的持久性。我们的项目将评估NKT细胞对记忆B细胞和浆细胞诱导和维护的影响。然后，我们将进行机械研究，以了解NKT细胞如何实现其对记忆B细胞和浆细胞的影响。我们的工作将促进对NKT细胞影响体液免疫反应的机制的理解，并可能突出发展新型疫苗策略的新机会。