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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：
8789151
负责人：
Hendrik Streeck
金额：
$ 28.1万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789151
关键词：
ALVAC Adaptor Signaling Protein Affect Affinity Antibodies Antibody Affinity Antibody Response 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 vaccine trial

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

描述（由申请人提供）：全世界有3300多万艾滋病毒-1感染，毫无疑问，迫切需要有效的艾滋病毒-1疫苗。在最近的RV144疫苗试验中观察到的适度和相当出乎意料的保护作用，即诱导非中和抗体，强调了对开发有效疫苗有必要进一步了解免疫学。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。虽然大多数许可疫苗诱导高亲和力抗体，但这些抗体的产生严重依赖于CD4+ T细胞的存在和作用。在这一过程中至关重要的是淋巴滤泡内的生发中心（GC）反应，其中T滤泡辅助细胞（TFH）亚群起着关键作用。GC中几个B细胞和CD4+ T细胞受体的精细调节相互作用对B细胞成熟、增殖和抗体类型转换至关重要。然而，目前对TFH细胞的作用和功能及其在控制病毒感染中的作用知之甚少。此外，人们对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）介导的其他受体之间的相互作用。SAP中的突变会导致致命的免疫缺陷，称为x连锁淋巴细胞增生性疾病。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的损伤，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。在这种情况下，在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。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的反应的诱导将对疫苗设计很重要。基于我们的初步研究结果，我们提出在特定目标#1中评估HIV-1感染受试者淋巴结中T滤泡辅助细胞的存在、功能和表型差异。在特定目标#2中，我们计划研究来自胃肠道的T滤泡辅助细胞反应是否能够诱导和促进抗HIV-1分泌IgA。在特定的目标#3中，我们计划研究CD4+和B细胞相互作用的特性，以及这种相互作用是否能够在受试者中产生中和抗体反应。因此，本研究旨在研究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保护产生的影响