Cubas Rafael, van Grevenynghe Julien, Wills Saintedym, Kardava Lela, Santich Brian H, Buckner Clarisa M, Muir Roshell, Tardif Virginie, Nichols Carmen, Procopio Francesco, He Zhong, Metcalf Talibah, Ghneim Khader, Locci Michela, Ancuta Petronella, Routy Jean-Pierre, Trautmann Lydie, Li Yuxing, McDermott Adrian B, Koup Rick A, Petrovas Constantinos, Migueles Steven A, Connors Mark, Tomaras Georgia D, Moir Susan, Crotty Shane, Haddad Elias K
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
Institut National de la Recherche Scientifique, Institut Armand-Frappier, Laval H7V 1B7, Quebec, Canada;
J Immunol. 2015 Dec 15;195(12):5625-36. doi: 10.4049/jimmunol.1501524. Epub 2015 Nov 6.
Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.
尽管抗逆转录病毒疗法（ART）在降低HIV感染者的病毒载量方面具有显著益处，但ART并不能完全恢复细胞免疫和体液免疫。接受ART治疗的HIV感染者对疫苗接种和感染的反应降低，并且在停止ART后无法产生有效的抗病毒免疫反应。许多因素导致了这些缺陷，包括持续性炎症，尤其是在淋巴组织中，T滤泡辅助（Tfh）细胞在其中指导并帮助B细胞启动有效的体液免疫反应。在本研究中，我们调查了循环记忆Tfh细胞的表型和功能，以此作为淋巴结中Tfh细胞的替代指标，发现慢性HIV感染者中这一细胞群体存在显著损伤，导致B细胞反应降低。我们进一步表明，这些异常的记忆Tfh细胞表现出白细胞介素-2（IL-2）反应性基因特征，并且更偏向于Th1表型。用IL-2处理功能性记忆Tfh细胞能够重现有害的重编程。重要的是，这种缺陷是可逆的，因为干扰IL-2信号通路有助于逆转异常分化并改善抗体反应。因此，HIV感染者记忆Tfh细胞的可逆重编程可用于增强抗体反应。淋巴组织中微环境条件的改变导致Tfh细胞分化改变，这可能是HIV感染者对新抗原反应性差的一种解释。这一解释对于开发治疗性干预措施以增强接受ART治疗患者的HIV和疫苗介导的抗体反应具有重要意义。
