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: 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
• 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

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）：毫无疑问，全球范围内有超过3,300万的HIV-1感染，迫切需要有效的HIV-1疫苗。在最近的RV144疫苗试验中观察到的谦虚且出乎意料的保护，引起了非中和抗体，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，RV144试验中使用的组合疫苗引起了强大的HIV-1特异性CD4+ T细胞反应。尽管大多数有执照的疫苗诱导高亲和力抗体，但这些抗体的产生主要取决于CD4+ T细胞的存在和作用。对这一过程的重要性是淋巴卵泡中的生发中心（GC）反应，其中T卵泡辅助器（TFH）细胞子群起着关键作用。 GC中几个B和CD4+ T细胞受体的精细调整相互作用对于B细胞成熟，增殖和抗体类切换至关重要。然而，目前，关于TFH细胞的作用和功能及其对病毒感染的控制的作用和功能知之甚少。此外，对于人类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。 SAP内的突变引起致命的免疫缺陷，称为X连锁淋巴增生性疾病。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害，但迄今为止尚不清楚TFH细胞是否受HIV-1感染影响。此外，重要的是要考虑大多数HIV感染是通过生殖器和直肠粘膜获得的，因此需要诱导强抗病毒免疫反应的主要部位。在这里，在感染过程中基本缺乏的局部抗HIV IgA反应可能最有效地防止感染。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细胞反应是粘膜生成IgA免疫力的关键组成部分，并且可以合理地相信，了解对艾滋病毒的诱导诱导对疫苗设计至关重要。根据我们的初步发现，我们在特定的目标＃1中提出，以评估具有HIV-1感染的受试者在特定目标2中的受试者淋巴结中T卵泡辅助细胞表型的存在，功能和差异。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，以及受试者中这种相互作用是否能够产生中和抗体反应。因此，该建议旨在研究HIV-1感染中B细胞和TFH细胞的中心相互作用及其对HIV-1保护对粘膜表面的影响的影响 公共卫生相关性（由申请人提供）：迫切需要全球3,300万HIV-1感染的人。默克疫苗试验的最新失败以及由两种候选疫苗（ALVAC/AIDSVAX;“泰国试验”）组合组成的疫苗的意外临时成功，这极大地证明了我们对如何开发有效疫苗的不良理解。尽管大多数有执照的疫苗诱导高亲和力抗体，但这些抗体的产生主要取决于CD4+ T细胞的存在和作用。特别是，生发中心内的T卵泡辅助细胞的作用对于诱导长寿命B细胞免疫至关重要。因此，在该提案中，我们旨在定义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。