Inadequate T follicular cell help impairs B cell immunity during HIV infection.
Inadequate T follicular cell help impairs B cell immunity during HIV infection.
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大多数艾滋病毒感染者不能产生保护性抗体，对免疫的反应减弱。我们报告说，即使有一个扩展的T滤泡辅助（Tfh）细胞在艾滋病毒感染的个人，这些是无法提供足够的B细胞的帮助。HIV感染者淋巴结中PD-L1+生发中心（GC）B细胞的频率较高，表明PD-1/PD-L1相互作用在调节Tfh细胞功能中具有潜在作用。事实上，PD-1在Tfh细胞上的参与导致细胞增殖、活化、ICOS表达和IL-21细胞因子分泌的减少。重要的是，阻断PD-1信号传导增强了体外HIV特异性免疫球蛋白的产生。我们进一步表明，这种缺陷的至少一部分涉及IL-21，因为添加这种细胞因子拯救了抗体应答和浆细胞生成。我们的研究结果表明，Tfh介导的B细胞的失调有助于减少HIV感染期间的B细胞反应，并可能与PD-1触发Tfh细胞有关。这些结果首次显示了Tfh细胞功能在HIV发病机制中的作用，并表明其功能的改变可能对HIV感染的结果和控制，未来的感染和疫苗接种产生重大影响。
The majority of HIV infected individuals fail to produce protective antibodies and have diminished responses to immunization. We report that even though there is an expansion of T follicular helper (Tfh) cells in HIV infected individuals, these are unable to provide adequate B cell help. A higher frequency of PD-L1+ germinal center (GC) B cells from lymph nodes of HIV infected individuals suggested a potential role for PD-1/PD-L1 interaction in regulating Tfh cell function. In fact, engagement of PD-1 on Tfh cells led to a reduction in cell proliferation, activation, ICOS expression and IL-21 cytokine secretion. Importantly, blocking PD-1 signaling enhanced HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21 as addition of this cytokine rescued antibody responses and plasma cell generation. Our results suggest that deregulation of Tfh-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on Tfh cells. These results show, for the first time, a role for Tfh cell function in HIV pathogenesis and suggest that an alteration in their function could have a significant impact on the outcome and control of HIV infection, future infections and vaccinations.