Regulation of humoral immunity by NKT cells

NKT细胞调节体液免疫

基本信息

  • 批准号:
    8013498
  • 负责人:
  • 金额:
    $ 32.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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抗原特异性记忆B细胞和长寿命的抗体分泌浆细胞来刺激长期中和抗体反应。为了在未来开发更有效的抗体刺激疫苗,我们需要提高我们对体液免疫诱导和维持机制的理解。我们报道了CD1d-限制性NKT细胞在免疫蛋白Ag时被CD1d结合糖脂1-半乳糖神经酰胺(1-GC)激活,导致抗体对该Ag的反应增强。从那时起,我们观察到NKT细胞在Ag的二次增强剂后增强了Ab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假设相一致的数据。尽管取得了这一进展,但目前还没有关于NKT细胞促进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。这些包括(i) nkt衍生的IL-5,支持浆细胞诱导;(ii) nkt表达的CD154 a配体,用于B细胞上表达的CD40,可能对诱导初级Ab反应和记忆B细胞很重要;(iii) TNF家族成员BAFF (B细胞活化因子),促进浆细胞的发育和存活。在本提案中,我们将研究NKT细胞影响体液免疫反应的机制。假设和目的:我们将验证NKT细胞来源的细胞因子、CD154和浆细胞生存因子BAFF通过支持记忆B细胞和长寿命浆细胞池的诱导和维持而在体液免疫反应中发挥重要作用的假设。在特异性目标1中,我们将评估cd1依赖性NKT激活和NKT缺失对体液免疫反应的影响。在特异性目标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。在特异性靶3中,我们将确定nkt衍生的BAFF是否会影响长寿命ag特异性浆细胞的诱导。我们将阐明NKT细胞支持和增强诱导和维持体液免疫反应的机制,从而整合两个先前不同的研究领域,并为两者做出重大贡献。我们的发现将有助于理解体液免疫,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由保护性抗体介导的长期体液免疫反应。尽管在了解体液免疫的诱导和维持机制方面取得了显著进展,但仍有许多东西需要学习。如果我们将来要针对没有疫苗的剩余病原体研制新型疫苗,这一点尤为重要。我们发现NKT细胞的激活增强了原代和召回抗体反应。我们的数据表明,这是由于增加了记忆B细胞(抗体分泌浆细胞的前体)的产生,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机制的理解,并可能突出开发新疫苗策略的新机会。

项目成果

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Mark L Lang其他文献

Mark L Lang的其他文献

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{{ truncateString('Mark L Lang', 18)}}的其他基金

Oklahoma C. difficile U19 Administrative Core
俄克拉荷马州艰难梭菌 U19 管理核心
  • 批准号:
    10625173
  • 财政年份:
    2023
  • 资助金额:
    $ 32.16万
  • 项目类别:
Functions of human C. difficile-specific memory B cell-derived monoclonal antibodies
人艰难梭菌特异性记忆 B 细胞来源的单克隆抗体的功能
  • 批准号:
    10625176
  • 财政年份:
    2023
  • 资助金额:
    $ 32.16万
  • 项目类别:
Advancing a second generation C. difficile vaccine
推进第二代艰难梭菌疫苗
  • 批准号:
    10625172
  • 财政年份:
    2023
  • 资助金额:
    $ 32.16万
  • 项目类别:
Activation of semi-invariant and diverse NKT cells with an adjuvant combination
使用佐剂组合激活半不变且多样化的 NKT 细胞
  • 批准号:
    10053313
  • 财政年份:
    2017
  • 资助金额:
    $ 32.16万
  • 项目类别:
Activation of semi-invariant and diverse NKT cells with an adjuvant combination
使用佐剂组合激活半不变且多样化的 NKT 细胞
  • 批准号:
    10291409
  • 财政年份:
    2017
  • 资助金额:
    $ 32.16万
  • 项目类别:
Regulation of humoral immunity by NKT cells
NKT细胞调节体液免疫
  • 批准号:
    7649089
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
Regulation of humoral immunity by NKT cells
NKT细胞调节体液免疫
  • 批准号:
    8417690
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
ENHANCEMENT OF HUMORAL IMMUNE RESPONSES BY CD1D-RESTRICTED NKT CELLS
CD1D 限制性 NKT 细胞增强体液免疫反应
  • 批准号:
    7959339
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
Regulation of humoral immunity by NKT cells
NKT细胞调节体液免疫
  • 批准号:
    8210923
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
Regulation of humoral immunity by NKT cells
NKT细胞调节体液免疫
  • 批准号:
    7766992
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:

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