CD1d and NKT Cell Activation and Function in Infection

描述（由申请人提供）：CD1d和NKT细胞在宿主防御许多微生物感染中的作用正在出现新的见解。在这些感染中，微生物脂质抗原由CD1d呈递，并由不变(i)NKT细胞表达的半不变T细胞受体（TCR）识别。这被称为直接的外源抗原驱动的iNKT细胞活化。这是一个重要的机制，但对于许多可以激活iNKT细胞的微生物来说，它可能不适用，因为它们不含有这种同源脂质抗原。例如，病毒、某些细菌和真菌（如这里所研究的）可能不含iNKT细胞抗原。这使我们确定了iNKT细胞激活的另一种独立于微生物脂质抗原识别的机制。微生物TLR激动剂刺激抗原呈递细胞（APC）分泌IL-12等细胞因子，而不是脂质抗原，这些细胞因子与APC上CD1d结合的自身脂质抗原提供的较弱的TCR刺激协同作用。在没有iNKT细胞TCR识别微生物脂质抗原的情况下，这些组合的信号协同引起强烈的iNKT细胞活化。我们称这种机制为间接的，细胞因子驱动的iNKT细胞激活。真菌引起多种重要疾病，包括局部和全身感染，并介导人类的特应性反应。我们发现几种常见的真菌病原体如白色念珠菌和烟曲霉能有效地激活iNKT细胞。然而，我们没有发现能被iNKT细胞识别的真菌脂质抗原。此外，真菌与细菌不同，因为它们含有表征不佳的TLR激动剂。真菌如何激活iNKT细胞以及NKT细胞在控制主要真菌感染中的作用在很大程度上是未知的。在这里，我们的初步数据显示真菌显著激活iNKT细胞，并且似乎使用细胞壁中复杂多糖介导的机制，如典型的2-葡聚糖，而不是真菌脂质抗原。此外，这些真菌多糖通过c型凝集素受体Dectin-1传递信号，而不是TLR信号。在这里，我们建议通过一组主要真菌，包括烟曲霉、白色念珠菌和新生念珠菌，在体外（目的1）和体内（目的2）定义iNKT细胞激活的分子基础，然后揭示iNKT细胞在体内控制侵袭性真菌感染方面未被认识到的核心作用（目的3）。总之，这些研究将为真菌如何通过其独特的多糖和CD1d呈现自脂质抗原来激活iNKT细胞提供新的见解。然后，我们将确定iNKT细胞如何协调先天白细胞如中性粒细胞和单核细胞的募集和激活，并影响后来的适应性CD4+ T细胞反应来控制真菌感染。

DESCRIPTION (provided by applicant): New insights are emerging into the role of CD1d and NKT cells in host defense against many microbial infections. In some of these infections, microbial lipid antigens are presented by CD1d and recognized by the semi-invariant T cell receptor (TCR) expressed by invariant (i)NKT cells. This is called direct, foreign antigen-driven iNKT cell activation. This is an important mechanism, but for many microbes that can activate iNKT cells it may not apply since they do not contain such cognate lipid antigens. For example, viruses, certain bacteria and fungi (as studied here) may not contain iNKT cell antigens. This led us to identify another mechanism of iNKT cell activation that is independent of recognition of microbial lipid antigens. Instead of lipid antigens, microbial TLR agonists stimulate antigen-presenting cells (APC) to secrete cytokines like IL-12 that synergize with weaker TCR stimulation provided by CD1d bound self-lipid antigens on the APC. These combined signals synergize to evoke strong iNKT cell activation, in the absence of iNKT cell TCR recognition of microbial lipid antigens. We call this mechanism indirect, cytokine-driven iNKT cell activation. Fungi cause a variety of important diseases, including local and systemic infections and mediate atopy in humans. We have found that several common fungal pathogens such as Candida albicans and Aspergillus fumigatus efficiently activate iNKT cells. Yet, we could identify no fungal lipid antigens that were recognized by iNKT cells. Moreover, fungi are different from bacteria as they contain poorly characterized TLR agonists. How fungi might activate iNKT cells and what role NKT cells play in control of major fungal infections in largely unknown. Here, our preliminary data reveal that fungi strikingly activate iNKT cells and appear to use a mechanism mediated by complex polysaccharides in their cells walls such as the characteristic 2-glucans, rather than fungal lipid antigens. Further, instead of TLR signaling, these fungal polysaccharides signal via the C-type lectin receptor, Dectin-1. Here we propose to define the molecular basis of iNKT cell activation by a panel of major fungi including A. fumigatus, C. albicans and C. neoformans in vitro (Aim 1) and in vivo (Aim 2) and then bring to light an unappreciated central role for iNKT cells in control of invasive fungal infection in vivo (Aim 3). Together, these studies will provide new insights into the how fungi active iNKT cells via their distinct polysaccharides and CD1d presented self-lipid antigens. Then we will determine how iNKT cells orchestrate the recruitment and activation of innate leukocytes like neutrophils and monocytes and impact the later adaptive CD4+ T cell response to control the fungal infection.