Regulation of humoral immunity by NKT cells

描述(由申请人提供)：我们最有效的疫苗通过刺激免疫系统来维持抗原特异性记忆B细胞和长期分泌抗体的浆细胞，从而刺激长期的中和抗体反应。为了在未来开发更有效的抗体刺激疫苗，我们需要提高对体液免疫诱导和维持机制的理解。我们报道了CD1d结合的糖脂1-半乳糖基神经酰胺(1-GC)在蛋白Ag免疫时激活CD1d限制性NKT细胞，导致对该抗原的抗体应答增强。从那时起，我们已经观察到，NKT细胞在用Ag进行第二次增强后，增强了抗体回忆反应。我们还获得了与NKT细胞增强记忆B细胞诱导和浆细胞寿命的结果相一致的数据，即回忆反应是NKT细胞增强记忆B细胞诱导和浆细胞寿命的结果。尽管取得了这一进展，但目前还没有关于NKT细胞有助于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反应。包括(1)NKT来源的IL-5，支持浆细胞的诱导；(2)NKT表达的CD154，CD40的配体，表达在B细胞上，可能对诱导原代抗体反应和记忆B细胞很重要；(3)肿瘤坏死因子家族成员BAFF(B细胞激活因子)，促进浆细胞的发育和存活。在这项建议中，我们将研究NKT细胞影响体液免疫反应的机制。假设和目的：我们将验证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细胞和长寿浆细胞池的诱导和维持而显著促进体液免疫反应的假设。在具体目标1中，我们将评估依赖CD1d的NKT激活和NKT缺失对体液免疫反应的影响。在特定的目标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。在具体目标3中，我们将确定NKT来源的BAFF是否影响长寿命的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反应的诱导和维持的机制，从而整合了两个先前不同的研究领域，并对两者都做出了重大贡献。我们的发现将对理解体液免疫有价值，并可能有助于设计包含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保护性抗体介导的长寿体液免疫反应。尽管在理解体液免疫诱导和维持机制方面取得了显著进展，但仍有许多需要学习的地方。如果我们要在未来开发针对尚无疫苗的剩余病原体的新型疫苗，这一点尤其重要。我们已经发现，NKT细胞的激活增强了一次抗体和回忆抗体反应。我们的数据表明，这是由于增加了记忆B细胞的产生，而记忆B细胞是分泌抗体的浆细胞的前体，并增加了浆细胞的持久性。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，并可能为开发新的疫苗策略提供新的机会。

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.