A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers.
A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers.
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DOI：
10.1128/mbio.00317-18
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发表时间：
2018-05-08
期刊：
影响因子：
6.4
通讯作者：
Chakrabarti LA
中科院分区：
文献类型：
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作者：
Claireaux M;Galperin M;Benati D;Nouël A;Mukhopadhyay M;Klingler J;de Truchis P;Zucman D;Hendou S;Boufassa F;Moog C;Lambotte O;Chakrabarti LA
滤泡辅助性T细胞(TFH)通过为B细胞提供帮助，在抗体反应的亲和力成熟过程中发挥重要作用。为了确定这种CD4+T细胞亚群是否有助于自发控制HIV感染，我们分析了来自ANRS CO21 Codex队列的患者的循环Tfh(CTfh)的表型和功能，这些患者自然地将HIV-1复制控制到无法检测的水平，并将他们与同样低病毒载量的接受治疗的患者进行了比较。CD45RA CD45RACDXCR5+−+T细胞中主要组织相容性复合体II类(MHC-II)四聚体标记检测到的HIV特异性CTFH(Tet+)在对照组中发生率较高(P=0.002)。两组患者Tet+cTfh中PD-1的表达频率(中位数为75%)较总cTfh中的表达频率(30%)增加，但治疗组的每细胞PD-1表达强度仍较高(P=0.02)，表明治疗患者持续存在异常免疫激活。在与自体记忆B细胞共培养中，cTfh的功能通过促进免疫球蛋白分泌的能力进行分析，在总免疫球蛋白生成方面，两组之间没有重大差异，但在测量HIV特异性免疫球蛋白生成时，对照组明显更有效。Tet+cTfh的频率与HIV特异性免疫球蛋白的产生相关(GAG特异性的R=0.71，环境特异性的R=0.79)。综上所述，我们的发现表明，关键的cTfh-B细胞相互作用在受控的HIV感染中被保留，导致强大的记忆B细胞反应，这可能在HIV控制中发挥被低估的作用。在没有治疗的情况下自发控制艾滋病毒复制的罕见患者提供了一种独特的模式，以确定有效的抗艾滋病毒免疫反应的决定因素。HIV控制者表现出特别有效的抗病毒T细胞反应的迹象，而直到最近，他们的体液反应还被认为在病毒控制中只起到了很小的作用。然而，新出现的证据表明，HIV控制者维持着一个重要的但“沉默的”抗病毒记忆B细胞群，可以在抗原刺激后重新激活。我们报告说，cTfh帮助可能有助于控制器记忆B细胞反应的持久性，因为HIV特异性cTfh的频率与功能分析中HIV特异性抗体的诱导有关。这些发现表明，T滤泡的帮助可能有助于艾滋病毒的控制，并强调了在旨在诱导持久B细胞反应的艾滋病毒疫苗策略中诱导这种帮助的必要性。
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 (P = 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 (P = 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 (R = 0.71 for Gag-specific and R = 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.