T follicular helper cells: Role in generation of anti-HIV antibody responses

滤泡辅助 T 细胞：在产生抗 HIV 抗体反应中的作用

基本信息

批准号：
8223231
负责人：
Hendrik Streeck
金额：
$ 13.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-10 至 2012-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223231
关键词：
ALVAC Adaptor Signaling Protein Affect Affinity Antibodies Antibody Affinity Antibody Formation Antiviral Agents B-Cell Activation B-Lymphocytes CD4 Positive T Lymphocytes Cell Communication Cell Lineage Cell Maturation Cells Combined Vaccines Defect Development Disease Engineering Exclusion Failure Family Gastrointestinal tract structure Generations Genes Genital system Goals HIV HIV Antibodies HIV Infections HIV vaccine HIV-1 Health Helper-Inducer T-Lymphocyte Hepatitis B Homing Human Humoral Immunities Immune response Immunity Immunoglobulin Class Switching Immunologic Deficiency Syndromes Impairment Individual Infection Infection prevention Intestines Invaded Knowledge Licensing Life Lymphoid Follicle Measles Measurable Mediating Memory B-Lymphocyte Mucosal Immunity Mucous Membrane Mutation Phenotype Plasma Plasma Cells Plasmablast Play Process Progressive Disease Property Proteins Reaction Role Signal Transduction Site Structure of germinal center of lymph node Surface T cell response T-Cell Receptor T-Lymphocyte TGFB1 gene Th1 Cells Time Uncertainty Vaccination Vaccine Design Vaccine Research Vaccines Viral Virus Virus Diseases X-Linked lymphoproliferative disorders Yellow Fever base cytokine design high risk lymph nodes neutralizing antibody pathogen prophylactic protective effect receptor rectal response success theories vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): With over 33 million HIV-1 infections world-wide, there is no doubt that an effective HIV-1 vaccine is urgently needed. The modest and quite unexpected protection observed in the recent RV144 vaccine trial, inducing non-neutralizing antibodies, underscores the necessity of greater immunological understanding to the development of an effective vaccine. Of particular note is that the combination vaccine used in the RV144 trial elicited a robust HIV-1-specific CD4+ T cell response. Although most licensed vaccines induce high-affinity antibodies, the generation of these antibodies is critically dependent on the presence and action of CD4+ T cells. Of central importance to this process is the germinal center (GC) reaction within the lymphoid follicles, wherein the T follicular helper (TFH) cell subset plays a key role. The finely-tuned interplay of several B- and CD4+ T- cell receptors in the GC is vital for B cell maturation, proliferation, and antibody class switching. Yet at present very little is known about the role and function of TFH cells or their contribution to the control of viral infections. Moreover, little is known about the basic immunological interactions between B cells and TFH cells in humans. Recent studies demonstrated that B and TFH cells undergo a tight initial interaction, which is among other receptors mediated by the SLAM-associated protein (SAP). Mutations within SAP cause a lethal immunodeficiency, called X-linked lymphoproliferative disease. Interestingly, although early studies described an impairment of germinal center formation in progressive HIV-1 disease, it is to date unknown whether TFH cells are affected by HIV-1 infection. Moreover, it is important to consider that most HIV infections are acquired through the genital and rectal mucosa and therefore the primary sites in which a strong antiviral immune response needs to be induced. Here, local anti-HIV IgA responses that are largely absent during infection are likely to be most effective to prevent infection. The critical signals for the generation of anti-IgA antibodies are a result of TFH and B cell interactions. Thus, TFH cell responses are a key component for the generation of IgA immunity at the mucosa, and it is reasonable to believe that an understanding of the induction of these responses against HIV will be important for vaccine design. Based on our preliminary findings, we propose in specific aim #1 to assess the presence, function and differences in the phenotype of T follicular helper cells in the lymph nodes of subjects with HIV-1 infection In specific aim #2 we plan to investigate whether T follicular helper cell responses from the gastrointestinal tract are able to induce and promote anti-HIV-1 secretory IgA. In specific aim #3, we plan to investigate the properties of the CD4+ and B cell interaction, and whether this interaction in subjects enables the generation of neutralizing antibody responses. Thus, this proposal aims to study the central interaction of B cells and TFH cells in HIV-1 infection and its impact on the generation of HIV-1 protection on mucosal surfaces PUBLIC HEALTH RELEVANCE (provided by applicant): With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX; "Thai trial") drastically demonstrate our poor understanding of how to develop an effective vaccine. Although most licensed vaccines induce high-affinity antibodies, the generation of these antibodies is critically dependent on the presence and action of CD4+ T cells. In particular the action of T follicular helper cells within the germinal center is critical for the induction of long-lived B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific TFH cells in the control of HIV-1 infection and their ability to induce protective immunity on mucosal surfaces.

描述（由申请人提供）：全世界有超过 3300 万 HIV-1 感染者，毫无疑问迫切需要一种有效的 HIV-1 疫苗。最近的 RV144 疫苗试验中观察到的适度且相当出乎意料的保护作用，诱导非中和抗体，强调了对开发有效疫苗需要更深入的免疫学了解的必要性。特别值得注意的是，RV144 试验中使用的联合疫苗引发了强烈的 HIV-1 特异性 CD4+ T 细胞反应。尽管大多数获得许可的疫苗都会诱导高亲和力抗体，但这些抗体的产生严重依赖于 CD4+ T 细胞的存在和作用。此过程中最重要的是淋巴滤泡内的生发中心 (GC) 反应，其中滤泡辅助 T (TFH) 细胞亚群起着关键作用。 GC 中几种 B- 和 CD4+ T 细胞受体的精细相互作用对于 B 细胞成熟、增殖和抗体类别转换至关重要。然而，目前人们对 TFH 细胞的作用和功能或其对控制病毒感染的贡献知之甚少。此外，人们对人类 B 细胞和 TFH 细胞之间的基本免疫相互作用知之甚少。最近的研究表明，B 细胞和 TFH 细胞经历了紧密的初始相互作用，这是由 SLAM 相关蛋白 (SAP) 介导的其他受体之一。 SAP 内的突变会导致致命的免疫缺陷，称为 X 连锁淋巴组织增生性疾病。有趣的是，尽管早期研究描述了进行性 HIV-1 疾病中生发中心形成受损，但迄今为止尚不清楚 TFH 细胞是否受到 HIV-1 感染的影响。此外，重要的是要考虑到大多数艾滋病毒感染是通过生殖器和直肠粘膜获得的，因此是需要诱导强烈抗病毒免疫反应的主要部位。在这里，感染期间基本不存在的局部抗 HIV IgA 反应可能是预防感染最有效的方法。产生抗 IgA 抗体的关键信号是 TFH 和 B 细胞相互作用的结果。因此，TFH 细胞反应是粘膜产生 IgA 免疫的关键组成部分，有理由相信，了解这些针对 HIV 的反应的诱导对于疫苗设计非常重要。根据我们的初步发现，我们在具体目标#1中建议评估HIV-1感染者淋巴结中滤泡辅助T细胞的存在、功能和表型差异。在具体目标#2中，我们计划调查是否来自胃肠道的滤泡辅助 T 细胞反应能够诱导和促进抗 HIV-1 分泌型 IgA。在具体目标 3 中，我们计划研究 CD4+ 和 B 细胞相互作用的特性，以及受试者中的这种相互作用是否能够产生中和抗体反应。因此，本提案旨在研究B细胞和TFH细胞在HIV-1感染中的核心相互作用及其对粘膜表面HIV-1保护生成的影响公共卫生相关性（由申请人提供）：全世界有 3300 万 HIV-1 感染者，迫切需要 HIV-1 疫苗。默克公司疫苗试验最近的失败以及由两种候选疫苗组合而成的疫苗（ALVAC/AIDSVAX；“泰国试验”）意外取得的成功，极大地表明了我们对如何开发有效疫苗的了解不足。尽管大多数获得许可的疫苗都会诱导高亲和力抗体，但这些抗体的产生严重依赖于 CD4+ T 细胞的存在和作用。特别是生发中心内滤泡辅助 T 细胞的作用对于诱导长效 B 细胞免疫至关重要。因此，在本提案中，我们的目标是定义 HIV-1 特异性 TFH 细胞在控制 HIV-1 感染中的作用及其在粘膜表面诱导保护性免疫的能力。