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

• 批准号: 8115504
• 负责人: Hendrik Streeck
• 金额: $ 44.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115504
• 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; 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

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，迫切需要有效的HIV-1疫苗。在最近的RV 144疫苗试验中观察到的适度和相当意外的保护，诱导非中和抗体，强调了对有效疫苗开发的更多免疫学理解的必要性。特别值得注意的是，RV 144试验中使用的联合疫苗引起了强烈的HIV-1特异性CD 4 + T细胞应答。虽然大多数许可的疫苗诱导高亲和力抗体，但这些抗体的产生严重依赖于CD 4 + T细胞的存在和作用。对该过程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（TFH）细胞亚群起关键作用。GC中几种B-和CD 4 + T-细胞受体的精细调节的相互作用对于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，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内的突变导致致命的免疫缺陷，称为X连锁淋巴增生性疾病。有趣的是，虽然早期的研究描述了在进行性HIV-1疾病中生发中心形成的损害，但迄今为止还不清楚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HIV感染是通过生殖器和直肠粘膜获得的，因此是需要诱导强抗病毒免疫应答的主要部位。在这里，在感染期间基本上不存在的局部抗HIV伊加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细胞应答是粘膜产生伊加免疫的关键组成部分，并且有理由相信，理解这些针对HIV的应答的诱导对于疫苗设计将是重要的。基于我们的初步发现，我们在具体目标#1中提出评估HIV-1感染受试者淋巴结中T滤泡辅助细胞表型的存在、功能和差异。在具体目标#2中，我们计划研究来自胃肠道的T滤泡辅助细胞应答是否能够诱导和促进抗HIV-1分泌型伊加。在具体目标#3中，我们计划研究CD 4+和B细胞相互作用的性质，以及受试者中的这种相互作用是否能够产生中和抗体应答。因此，本提案旨在研究HIV-1感染中B细胞和TFH细胞的中心相互作用及其对粘膜表面HIV-1保护作用的影响 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。最近默克疫苗试验的失败和由两种候选疫苗组合组成的疫苗（ALVAC/AIDSVAX;“泰国试验”）的意外适度成功彻底证明了我们对如何开发有效疫苗的理解不足。虽然大多数许可的疫苗诱导高亲和力抗体，但这些抗体的产生严重依赖于CD 4 + T细胞的存在和作用。特别地，生发中心内的T滤泡辅助细胞的作用对于诱导长寿的B细胞免疫至关重要。因此，在本提案中，我们的目标是确定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。