单基因变异对人类原发性免疫缺陷患者中T滤泡辅助细胞的数量和质量有不同影响。

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

作者信息

Ma Cindy S, Wong Natalie, Rao Geetha, Avery Danielle T, Torpy James, Hambridge Thomas, Bustamante Jacinta, Okada Satoshi, Stoddard Jennifer L, Deenick Elissa K, Pelham Simon J, Payne Kathryn, Boisson-Dupuis Stéphanie, Puel Anne, Kobayashi Masao, Arkwright Peter D, Kilic Sara Sebnem, El Baghdadi Jamila, Nonoyama Shigeaki, Minegishi Yoshiyuki, Mahdaviani Seyed Alireza, Mansouri Davood, Bousfiha Aziz, Blincoe Annaliesse K, French Martyn A, Hsu Peter, Campbell Dianne E, Stormon Michael O, Wong Melanie, Adelstein Stephen, Smart Joanne M, Fulcher David A, Cook Matthew C, Phan Tri Giang, Stepensky Polina, Boztug Kaan, Kansu Aydan, İkincioğullari Aydan, Baumann Ulrich, Beier Rita, Roscioli Tony, Ziegler John B, Gray Paul, Picard Capucine, Grimbacher Bodo, Warnatz Klaus, Holland Steven M, Casanova Jean-Laurent, Uzel Gulbu, Tangye Stuart G

机构信息

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.

出版信息

J Allergy Clin Immunol. 2015 Oct;136(4):993-1006.e1. doi: 10.1016/j.jaci.2015.05.036. Epub 2015 Jul 7.

DOI:10.1016/j.jaci.2015.05.036

PMID:26162572

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5042203/

Abstract

BACKGROUND

Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.

OBJECTIVE

We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.

METHODS

Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.

RESULTS

Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.

CONCLUSION

Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

摘要

背景

滤泡辅助性T（TFH）细胞是T细胞依赖性体液免疫及大多数疫苗成功接种的基础。TFH细胞也与人类免疫紊乱有关，如自身免疫、免疫缺陷和恶性肿瘤。了解TFH细胞生成和功能的分子需求将为靶向这些细胞以调节其在这些免疫异常情况下的行为提供策略。

目的

我们试图确定人类受试者中TFH细胞发育和功能所需的信号通路及细胞间相互作用。

方法

由单基因突引起的人类原发性免疫缺陷病（PID）为评估特定分子对调节人类淋巴细胞功能的需求提供了独特机会。对健康对照受试者以及因STAT3、STAT1、TYK2、IL21、IL21R、IL10R、IFNGR1/2、IL12RB1、CD40LG、NEMO、ICOS或BTK基因突变导致PID的患者，定量分析循环滤泡辅助性T（cTFH）细胞亚群、记忆B细胞和血清免疫球蛋白水平，并进行功能评估。

结果

STAT3、IL10R、CD40LG、NEMO、ICOS或BTK的功能丧失（LOF）突变降低了cTFH细胞频率。STAT3和IL21/R的LOF以及STAT1的功能获得性突变使cTFH细胞分化偏向以IFN-γ和程序性死亡1过表达为特征的表型。IFN-γ在体外和体内均抑制cTFH细胞功能，IFNGR1/2、STAT1和IL12RB1 LOF突变患者的高球蛋白血症证实了这一点。

结论

特定突变会影响cTFH细胞的数量和质量，凸显了通过使用包括表型和功能在内的多种标准评估患者TFH细胞的必要性。此外，IFN-γ在体内发挥作用以抑制TFH细胞诱导的B细胞分化。这些发现为TFH细胞生物学及其生成、维持和效应功能所需的整合信号通路提供了新见解，并解释了一些PID患者出现的体液免疫受损情况。