Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), Duke University, Durham, North Carolina, USA.
JCI Insight. 2017 Jan 26;2(2):e89574. doi: 10.1172/jci.insight.89574.
HIV-1-specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5CXCR3PD-1 CD4 T cells. These CXCR3PD-1 Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3PD-1 Tfh-like cells contained higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1 Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5CXCR3PD-1 cells represent a dendritic cell-primed precursor cell population for PD-1 Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia.
HIV-1 特异性广谱中和抗体（bnAbs）通常在持续高水平病毒复制和免疫激活增加的个体中产生，而这些条件在预防性免疫接种中无法复制。了解在没有高水平病毒血症的情况下支持 bnAb 发展的机制对于设计 bnAb 诱导免疫原可能很重要。在这里，我们表明，HIV-1 控制者中和抗体反应的广度与循环 CXCR5CXCR3PD-1 CD4 T 细胞的相对富集有关。这些 CXCR3PD-1 Tfh 样细胞在体外主要由控制器中和者的功能优越的树突状细胞诱导产生，并且能够分泌 IL-21 并支持 B 细胞。此外，这些 CXCR3PD-1 Tfh 样细胞含有更高比例的干细胞样记忆 T 细胞，并且在抗原刺激下以 Notch 依赖性方式分化为 PD-1 Tfh 样细胞。总之，这些数据表明，CXCR5CXCR3PD-1 细胞代表 PD-1 Tfh 样细胞的树突状细胞激活前细胞群体，可能有助于在没有高水平病毒血症的情况下产生 bnAbs。
