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 细胞和长寿命的抗体分泌浆细胞来刺激长期中和抗体反应。为了将来开发出更有效的抗体刺激疫苗，我们需要加深对体液免疫诱导和维持机制的理解。我们报道，在用蛋白质Ag免疫时，用CD1d结合糖脂1-半乳糖神经酰胺(1-GC)激活CD1d限制性NKT细胞，导致Ab对该Ag的反应增强。从那时起，我们观察到 NKT 细胞在使用 Ag 进行二次加强后增强了 Ab 回忆反应。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。尽管取得了这一进展，但目前尚无关于 NKT 细胞促进体液免疫诱导和维持的机制的报道。我们的初步数据表明 NKT 细胞利用多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，是 B 细胞上表达的 CD40 的配体，可能对诱导初级抗体反应和记忆 B 细胞很重要 (iii) TNF家族成员 BAFF（B 细胞激活因子），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。假设和目标：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 细胞和长寿命浆细胞库的诱导和维持，对体液免疫反应做出重大贡献。在具体目标 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。在具体目标 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 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反应的诱导和维持的机制，从而整合两个先前不同的研究领域，并对这两个领域做出重大贡献。我们的研究结果对于理解体液免疫很有价值，并可能有助于设计结合 NKT 激活的新型疫苗接种策略。公共卫生相关性：大多数成功的疫苗都会刺激由保护性抗体介导的长期体液免疫反应。尽管在理解体液免疫诱导和维持机制方面取得了显着进展，但仍有很多东西需要学习。如果我们将来要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。我们发现 NKT 细胞的激活可增强初级和回忆抗体反应。我们的数据表明，这是由于记忆 B 细胞（分泌抗体的浆细胞的前体）的产生增加以及浆细胞的持久性增加所致。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 细胞如何实现对记忆 B 细胞和浆细胞的影响。我们的工作将增进对 NKT 细胞影响体液免疫反应机制的理解，并可能凸显开发新型疫苗策略的新机会。