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

描述(申请人提供)：全世界有超过3300万人感染艾滋病毒-1，毫无疑问，迫切需要一种有效的艾滋病毒-1疫苗。在最近的RV144疫苗试验中观察到的适度和相当意想不到的保护作用，诱导了非中和抗体，强调了更多地了解免疫学对开发有效疫苗的必要性。特别值得注意的是，RV144试验中使用的联合疫苗引起了强大的HIV-1特异性CD4T细胞反应。尽管大多数获得许可的疫苗都能诱导高亲和力抗体，但这些抗体的产生严重依赖于CD4T细胞的存在和作用。淋巴滤泡内的生发中心(GC)反应是这一过程的核心，其中T滤泡辅助细胞(TFH)亚群起着关键作用。GC中几种B和CD4T细胞受体的微调相互作用对B细胞的成熟、增殖和抗体类型的转换至关重要。然而，目前对TFH细胞的作用和功能以及它们在病毒感染控制中的作用知之甚少。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细胞和TFH细胞经历了一种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内的突变会导致一种致命的免疫缺陷，称为X连锁淋巴增殖性疾病。有趣的是，尽管早期的研究描述了进行性HIV-1疾病中生发中心形成的障碍，但至今尚不清楚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细胞反应是在粘膜产生IgA免疫的关键成分，有理由相信，了解这些针对HIV的反应的诱导将对疫苗设计至关重要。基于我们的初步发现，我们建议在特定目的#1中评估HIV-1感染者淋巴中T滤泡辅助细胞的存在、功能和表型差异。在特定目的#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，以及受试者这种相互作用是否能够产生中和抗体反应。因此，这项建议旨在研究B细胞和TFH细胞在HIV-1感染中的中枢相互作用及其对粘膜表面HIV-1保护作用的影响

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