IFN-α抑制骨髓细胞因子的产生，损害IL-12的产生以及支持T细

StephenW

J Infect Dis. 2020 Feb 12. pii: jiaa064. doi: 10.1093/infdis/jiaa064. [Epub ahead of print]
IFN-α Suppresses Myeloid Cytokine Production, Impairing IL-12 Production and the Ability to Support T cell Proliferation.
Mehrotra A1, D'Angelo JA2, Romney-Vanterpool A2, Chu T3, Bertoletti A4,5, Janssen HLA1, Gehring AJ1,6.
Author information

1
    Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
2
    Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
3
    Genentech, Safety Science, San Francisco, CA, USA.
4
    Program of Emerging Viral Diseases, Duke-NUS Medical School, Singapore.
5
    Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star), Singapore.
6
    Department of Immunology, University of Toronto, Toronto, Canada.

Abstract

IFN-α can suppress production of T cell polarizing cytokines or induce inhibitory antigen presenting cells that suppress T cell activation. Previous studies showed that IFN-α therapy fails to boost virus-specific T cell immunity in patients with chronic Hepatitis B virus (HBV) infection. Our aim was to determine whether IFN-α exposure alters human antigen presenting cell function in vivo. We investigated the immunomodulatory effects using healthy donor PBMC exposed to IFN-α, and chronic hepatitis B (CHB) patients starting IFN-α therapy. IFN-α increased HLA-DR, CD80, CD86 and PD-L1 expression on healthy donor monocytes. In contrast to the activated phenotype, IFN-α inhibited TLR-induced cytokine production and monocyte-induced T cell proliferation. In CHB patients, peg-IFN treatment induced an interferon-stimulated gene signature in monocytes and increased HLA-DR, CD80, CD86 and PD-L1 expression. As early as 3d after CHB patients started treatment, IFN-α inhibited monocyte cytokine production and T cell stimulation ex vivo. IFN-α-mediated inhibition of IL-12 production, rather than inhibitory receptor expression, was responsible for inhibition of T cell proliferation. Addition of IL-12 restored T cell proliferation to baseline levels. Understanding how professional antigen presenting cells respond to immunomodulation is important for both new innate and adaptive-targeted immunotherapies.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].
KEYWORDS:

Hepatitis B virus; IFN-α; Monocytes; antigen presenting cell

PMID:
    32049318
DOI:
    10.1093/infdis/jiaa064

StephenW

感染杂志2020年2月12日。pii：jiaa064。 Doi：10.1093 / infdis / jiaa064。 [Epub提前发行]
IFN-α抑制骨髓细胞因子的产生，损害IL-12的产生以及支持T细胞增殖的能力。
Mehrotra A1，D'Angelo JA2，Romney-Vanterpool A2，Chu T3，Bertoletti A4,5，Janssen HLA1，Gehring AJ1,6。
作者信息

1个
加拿大多伦多大学健康网络多伦多总医院研究所多伦多肝病中心。
2
圣路易斯大学医学院分子微生物学和免疫学，美国密苏里州圣路易斯。
3
Genentech，安全科学，美国加利福尼亚州旧金山。
4
新加坡杜克国大医学院新发病毒性疾病计划。
5
新加坡临床科学研究院，科学技术和研究机构（A *星），新加坡。
6
加拿大多伦多大学多伦多大学免疫学系。

抽象

IFN-α可以抑制T细胞极化细胞因子的产生或诱导抑制T细胞活化的抑制性抗原呈递细胞。先前的研究表明，对于慢性乙型肝炎病毒（HBV）感染的患者，IFN-α治疗无法增强病毒特异性T细胞免疫。我们的目的是确定IFN-α暴露是否在体内改变了人类抗原提呈细胞的功能。我们使用暴露于IFN-α的健康供体PBMC和开始IFN-α治疗的慢性乙型肝炎（CHB）患者，研究了其免疫调节作用。 IFN-α增加了健康供体单核细胞上HLA-DR，CD80，CD86和PD-L1的表达。与激活的表型相反，IFN-α抑制TLR诱导的细胞因子产生和单核细胞诱导的T细胞增殖。在CHB患者中，peg -IFN治疗诱导单核细胞中干扰素刺激的基因签名，并增加HLA-DR，CD80，CD86和PD-L1表达。早在CHB患者开始治疗后3天，IFN-α就抑制了单核细胞细胞因子的产生和离体T细胞的刺激。 IFN-α介导的IL-12产生抑制，而不是抑制性受体表达，是抑制T细胞增殖的原因。添加IL-12可将T细胞增殖恢复至基线水平。对于新的先天性和适应性靶向免疫疗法，了解专业的抗原呈递细胞如何对免疫调节作出反应非常重要。

©2020作者。牛津大学出版社，美国传染病学会。版权所有。有关权限，请发送电子邮件至：[email protected]。
关键字：

乙型肝炎病毒； IFN-α;单核细胞;抗原呈递细胞

PMID：
32049318
DOI：
10.1093 / infdis / jiaa064