Pasteur Institute, Viral Pathogenesis Unit, Paris, France.
INSERM U1108, Paris, France.
mBio. 2018 May 8;9(3):e00317-18. doi: 10.1128/mBio.00317-18.
Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4 T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA CXCR5 CD4 T cell population, proved more frequent in the controller group ( = 0.002). The frequency of PD-1 expression in Tet cTfh was increased in both groups (median, >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group ( = 0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet cTfh correlated with HIV-specific IgG production ( = 0.71 for Gag-specific and = 0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control. The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antiviral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but "silent" antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely contributes to the persistence of controller memory B cell responses, as the frequency of HIV-specific cTfh correlated with the induction of HIV-specific antibodies in functional assays. These findings suggest that T follicular help may contribute to HIV control and highlight the need for inducing such help in HIV vaccine strategies that aim at eliciting persistent B cell responses.
滤泡辅助 T 细胞（Tfh）通过向 B 细胞提供帮助，在抗体应答的亲和力成熟中发挥重要作用。为了确定这一 CD4 T 细胞亚群是否有助于 HIV 感染的自发性控制，我们分析了来自 ANRS CO21 CODEX 队列的自然控制 HIV-1 复制至无法检测水平的患者的循环滤泡辅助 T 细胞（cTfh）的表型和功能，并将其与具有相似低病毒载量的治疗患者进行了比较。通过 Gag-主要组织相容性复合物 II（MHC-II）四聚体标记在 CD45RA CXCR5 CD4 T 细胞群中检测到的 HIV 特异性 cTfh（Tet），在对照组中更为常见（=0.002）。与总 cTfh（<30%）相比，两组中 PD-1 在 Tet cTfh 中的表达频率均增加（中位数，>75%），但每个细胞的 PD-1 表达强度在治疗组中仍然较高（=0.02），这表明治疗患者中持续存在异常免疫激活。通过 Tet cTfh 促进与自体记忆 B 细胞共培养中 IgG 分泌的能力分析 cTfh 的功能，在总 IgG 产生方面，各组之间没有明显差异，但在测量 HIV 特异性 IgG 产生时，对照组的效率明显更高。Tet cTfh 的频率与 HIV 特异性 IgG 产生相关（Gag 特异性为=0.71，Env 特异性为=0.79）。综上所述，我们的研究结果表明，在受控制的 HIV 感染中，关键的 cTfh-B 细胞相互作用得以保留，从而导致有效的记忆 B 细胞反应，这可能在 HIV 控制中发挥了被低估的作用。在没有治疗的情况下自发控制 HIV 复制的极少数患者提供了一个独特的模型，可以识别有效的抗 HIV 免疫反应的决定因素。HIV 控制器表现出特别有效的抗病毒 T 细胞反应的迹象，而其体液反应直到最近才被认为在病毒控制中只起次要作用。然而，新出现的证据表明，HIV 控制器维持着一种重要但“沉默”的抗病毒记忆 B 细胞群体，在抗原刺激下可以被重新激活。我们报告说，cTfh 帮助可能有助于控制器记忆 B 细胞反应的持续存在，因为 HIV 特异性 cTfh 的频率与功能测定中 HIV 特异性抗体的诱导相关。这些发现表明滤泡辅助 T 细胞可能有助于 HIV 控制，并强调在旨在引起持续 B 细胞反应的 HIV 疫苗策略中需要诱导这种帮助。
