FOLLICULAR DENDRITIC CELLS AND IMMUNOSUPPRESSION IN AIDS

滤泡树突状细胞(FDC)在免疫调节中发挥重要作用 最近被发现是艾滋病毒沉积的地点。FDC服务 作为诱发和维持记忆障碍的长期银库 应答以及贡献Ag独立信号被认为是 是生发中心形成所必需的。为了使银(或 感染剂)与FDC相关，或者是特定的抗体 和/或需要补体激活。在其中一项或两项之后 事件发生时，免疫复合体或补体包被颗粒 形成并可被捕获在FDC的树枝状表面。很快就会 在FDC上捕获后，发生生发中心形成。这些生发 中心由高度活化和快速增殖的B(和 FDC周围的CD4+T)细胞。在艾滋病毒感染中，病毒颗粒迅速 与淋巴滤泡中的FDC相关，尽管其机制 这个协会的一部分尚未建立。一旦被困在FDC，病毒 定位于易感细胞所在的生发中心区域 处于高度活跃的状态。因此，艾滋病病毒在FDC上的定位显然 汇聚了成功和 CD4+T细胞的生产性感染，并使它们长时间保持在一起 民盟成员都出席了。我们假设FDC由于感染了HIV 而共刺激信号的产生在整个过程中起着至关重要的作用 艾滋病的发病机制，并建议使用体内和体内来测试这一点 体外模型。这项提案的具体目的是：1)确定是否 HIV可以专门针对FDC，如果这个目标是 通过补体激活、特异性抗体或其组合完成 2)确定携带HIV的FDC是否可以直接感染激活的 CD_4~+T细胞及HIV特异性抗体对此的影响 3)确定FDC和/或生发中心B 细胞可以提供足够的辅助细胞功能来促进 静息的CD4+T细胞的生产性感染。

Follicular dendritic cells (FDC) play a major role in immunoregulation and have recently been found to be a site of HIV deposition. FDC serve as long-term depots of Ag for induction and maintenance of anamnestic responses as well as contributing Ag independent signalling believed to be necessary for germinal center formation. In order for Ag (or infectious agents) to become associated with FDC, either specific Ab and/or complement activation is required. After one or both of these events have occurred, immune complexes or complement coated particles are formed and can be trapped on the dendritic surfaces of FDC. Shortly after trapping on FDC, germinal center formation occurs. These germinal centers are composed of highly activated and rapidly proliferating B (and CD4+ T) cells surrounding FDC. In HIV infection, viral particles quickly become associated with FDC in lymphoid follicles although the mechanism of this association has not been established. Once trapped on FDC, virus is localized to the germinal center area where susceptible cells reside in a highly activated state. Thus HIV localization on FDC apparently brings together all of the components needed for successful and productive infection of CD4 + T cells and keeps them together as long as the FDC are present. We hypothesize that FDC by virtue of trapped HIV and generation of costimulatory signals play a vital role In the pathogenesis of AIDS and propose to test this using both in vivo and in vitro models. The specific aims of this proposal are to: 1) determine if HIV can specifically target itself to FDC and if this targeting is accomplished by complement activation, specific Ab or a combination of both; 2) determine whether FDC bearing HIV can directly infect activated CD4 + T cells and to assess the contribution of HIV specific Ab on this infectious process; and 3) determine whether FDC and/or germinal center B cells can provide sufficient accessory cell function to promote productive infection of resting CD4 + T cells.