Regulation of humoral immunity by NKT cells

NKT细胞调节体液免疫

• 批准号: 8210923
• 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/8210923
• 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（由申请方提供）：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细胞和长寿命分泌Ab的浆细胞来刺激长期中和Ab应答。为了在未来开发更有效的Ab刺激疫苗，我们需要提高我们对体液免疫诱导和维持机制的理解。我们报道了在用蛋白质Ag免疫时用CD 1d结合糖脂1-半乳糖神经酰胺（1-GC）激活CD 1d限制性NKT细胞导致对该Ag的抗体应答增强。从那时起，我们已经观察到，NKT细胞增强抗体回忆反应后，第二次加强与Ag。我们还获得了与以下假设一致的数据：回忆反应是NKT细胞增强记忆B细胞诱导和浆细胞寿命的结果。尽管取得了这些进展，但目前还没有关于NKT细胞诱导和维持体液免疫的机制的报道。我们的初步数据表明，NKT细胞利用几种机制来诱导和维持有效的体液免疫应答。这些包括（i）支持浆细胞诱导的NKT衍生的IL-5（ii）NKT表达的CD 154，CD 154是在B细胞上表达的CD 40的配体，并且可能对诱导初级Ab应答和记忆B细胞很重要（iii）促进浆细胞发育和存活的TNF家族成员BAFF（B细胞活化因子）。在这个提议中，我们将研究NKT细胞影响体液免疫反应的机制。假设和目标：我们将检验NKT细胞衍生的细胞因子、CD 154和浆细胞存活因子BAFF通过支持记忆B细胞和长寿浆细胞池的诱导和维持而对体液免疫应答有实质性贡献的假设。在具体目标1中，我们将评估CD 1d依赖性NKT激活和NKT缺失对体液免疫应答的影响。在具体目标2中，我们将确定NKT衍生的IL-5和CD 154如何增强体液免疫应答。在特定目标3中，我们将确定NKT衍生的BAFF是否影响长寿命Ag特异性浆细胞的诱导。我们将阐明NKT细胞支持和增强体液免疫应答的诱导和维持的机制，从而整合两个以前不同的研究领域，并为两者做出重大贡献。我们的研究结果将是有价值的了解体液免疫，并可能有助于设计新的疫苗接种策略，将NKT激活。公共卫生相关性：大多数成功的疫苗刺激由保护性抗体介导的长寿命体液免疫应答。尽管在理解体液免疫的诱导和维持机制方面取得了显着进展，但仍有许多需要学习的东西。如果我们要在未来开发新的疫苗来对付没有疫苗的剩余病原体，这一点特别重要。我们已经发现NKT细胞的激活增强了初级和回忆抗体应答。我们的数据表明，这是由于增加了记忆B细胞的产生，抗体分泌浆细胞的前体，并通过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持的影响。然后，我们将进行机制研究，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，并可能突出开发新疫苗策略的新机会。