THE ROLE OF NK-22 CELLS IN ANTI-HIV-1 MUCOSAL IMMUNITY

NK-22 细胞在抗 HIV-1 粘膜免疫中的作用

• 批准号: 8469752
• 负责人: MARCO COLONNA
• 金额: $ 34.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-12 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469752
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Antibodies; Antibody Formation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Collaborations; Data; Disease; Generations; HIV; HIV-1; Helper-Inducer T-Lymphocyte; Human; Immune; Immune system; Immunity; Immunology; In Vitro; Individual; Infection; Inflammatory; Interleukin-7; Interleukins; Intestines; Knowledge; Mediating; Mediator of activation protein; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Natural Killer Cells; Nature; Oral; Pharmaceutical Preparations; Positioning Attribute; Property; Protocols documentation; Reagent; Role; Route; Site; Techniques; Therapeutic; Tonsil; Vaccine Adjuvant; Vaccines; Viral; Virus; base; cytokine; design; enhancing factor; improved; interleukin-22; novel; oral vaccine; precursor cell; public health relevance; research study; response; secondary infection

DESCRIPTION (provided by applicant): HIV-1 infection and mucosal immunity are intimately interrelated. Since the acquisition of HIV-1 primarily occurs through mucosal routes, local immunity at the site of infection is essential for controlling viral spread within the host and in transmitting virus to other individuals. Additionally, established HIV-1 infection compromises both innate and adaptive mucosal immunity, facilitating secondary infections and progression to acquired immune deficiency syndrome (AIDS). Thus, if we are to develop an effective vaccine for HIV-1 that protects the key target cells in the mucosa, we first need to understand how to induce protective anti-HIV-1 mucosal immune responses. We recently discovered a novel subset of tonsil and gut innate immune cells that express natural killer (NK) cell markers, but, in contrast to conventional NK cells, produce interleukin (IL)-22 and other cytokines that protect the integrity of the mucosal barriers during infectious and inflammatory diseases. We refer to these cells as NK-22 (Cella M, et al, Nature. 2009;457:722). Our preliminary data indicate that NK-22 cells directly counter HIV-1 replication in infected CD4 T cells in vitro. We also demonstrate that NK-22 cells secrete BAFF, a soluble factor that enhances B cell responses. Based on their unique properties, we propose that NK-22 cells may be crucial for innate and adaptive anti-HIV-1 mucosal responses. In our proposal we will determine the mechanisms by which NK-22 cells counter HIV-1 infection (specific aim 1), identify vaccine adjuvants that expand NK-22 cells in the mucosa (specific aim 2), and determine the impact of NK-22 cells on adaptive B cell responses against HIV-1 (specific aim 3). We are uniquely positioned to successfully address these aims because of our original discovery of human NK-22 cells, our broad expertise in NK cell biology, the strength of our preliminary data, the relatively straightforward experiments that we have chosen and the availability of reagents through our collaboration with the Center for HIV/AIDS Vaccine Immunology (CHAVI). Our proposal will significantly advance our knowledge of anti-HIV-1 mucosal immune responses and identify adjuvants that can be used to generate vaccines for HIV-1 that elicit effective mucosal immunity.

描述（由申请人提供）：HIV-1感染和粘膜免疫密切相关。由于HIV-1的获得主要通过粘膜途径发生，因此感染部位的局部免疫对于控制病毒在宿主内的传播和将病毒传播给其他个体至关重要。此外，确定的HIV-1感染损害先天和适应性粘膜免疫，促进继发性感染和进展为获得性免疫缺陷综合征（AIDS）。因此，如果我们要开发一种有效的HIV-1疫苗，保护粘膜中的关键靶细胞，我们首先需要了解如何诱导保护性抗HIV-1粘膜免疫应答。 我们最近发现了一种新的扁桃体和肠道先天免疫细胞亚群，它们表达自然杀伤（NK）细胞标志物，但与传统NK细胞相反，它们产生白细胞介素（IL）-22和其他细胞因子，在感染性和炎症性疾病期间保护粘膜屏障的完整性。我们将这些细胞称为NK-22（切拉M等人，Nature. 2009;457：722）。我们的初步数据表明，NK-22细胞在体外直接对抗感染的CD 4 T细胞中的HIV-1复制。我们还证明NK-22细胞分泌BAFF，一种增强B细胞应答的可溶性因子。 基于其独特的性质，我们认为NK-22细胞可能对先天性和适应性抗HIV-1粘膜反应至关重要。在我们的提案中，我们将确定NK-22细胞对抗HIV-1感染的机制（具体目标1），确定在粘膜中扩增NK-22细胞的疫苗佐剂（具体目标2），并确定NK-22细胞对适应性B细胞抗HIV-1应答的影响（具体目标3）。 由于我们最初发现了人类NK-22细胞，我们在NK细胞生物学方面的广泛专业知识，我们初步数据的力量，我们选择的相对简单的实验以及通过与HIV/AIDS疫苗免疫学中心（CHAVI）合作获得的试剂，我们处于独特的位置，能够成功实现这些目标。 我们的建议将显着推进我们的知识，抗HIV-1粘膜免疫反应，并确定佐剂，可用于产生疫苗的HIV-1，引起有效的粘膜免疫。