IL‐21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection,Immunology and Cell Biology

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IL‐21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-10-17 , DOI: 10.1111/imcb.12418
Rodrigo Benedetti Gassen _{1,

2,

3} , Tiago Fazolo _{1,

2} , Deise Nascimento de Freitas ₂ , Thiago J Borges ₃ , Karina Lima _{1,

4} , Géssica L Antunes ₂ , Fábio Maito ₅ , Daniel Ag Bueno Mendes ₆ , André Báfica ₆ , Luiz Carlos Rodrigues ₇ , Renato Stein ₈ , Ana Paula Duarte de Souza ₂ , Cristina Bonorino _{4,

9}

Affiliation

Laboratório de Imunologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
Laboratório de Imunologia Clínica e Experimental, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
Renal Division, Schuster Family Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Laboratório de Imunoterapia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
Laboratório de Histologia, Faculdade de Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
Laboratório de Imunobiologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Laboratório de Imunovirologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
Department of Surgery, School of Medicine, University of California at San Diego, La Jolla, CA, USA.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV‐specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL‐21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL‐21/interleukin‐21 receptor (IL‐21R) in Tfh cells and upregulated programmed death‐ligand 1 (PD‐L1) expression in dendritic cells (DCs) and B cells. PD‐L1 blockade during infection recovered IL‐21R expression in Tfh cells and increased the secretion of IL‐21 in a DC‐dependent manner. IL‐21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti‐RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL‐21‐treated RSV‐infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD‐L1 expression on antigen‐presenting cells, highlighting the importance of an IL‐21–PD‐L1 axis for the generation of protective responses to RSV infection.

中文翻译：

IL-21 治疗可恢复滤泡辅助 T 细胞并中和呼吸道合胞病毒感染中的抗体产生

呼吸道合胞病毒 (RSV) 是 1 岁以下儿童下呼吸道感染的主要原因。目前无法获得 RSV 疫苗，遭受同一病毒株多次再次感染的儿童无法产生保护性反应。尽管在感染时可以检测到 RSV 特异性抗体，但它们的中和能力有限。滤泡辅助性 T (Tfh) 细胞专门为 B 细胞提供信号并帮助抗体的产生和亲和力成熟，主要通过白细胞介素 (IL) 21 分泌。在这项研究中，我们评估了 RSV 是否可以抑制 Tfh 反应。我们观察到 Tfh 细胞在 RSV 感染后未能上调 IL-21 的产生。在肺部，RSV 感染下调 Tfh 细胞中 IL-21/白细胞介素 21 受体 (IL-21R) 的表达，并上调树突状细胞 (DC) 和 B 细胞中程序性死亡配体 1 (PD-L1) 的表达。感染期间的 PD-L1 阻断恢复了 Tfh 细胞中 IL-21R 的表达，并以 DC 依赖性方式增加了 IL-21 的分泌。IL-21 治疗降低 RSV 病毒载量和肺部炎症，诱导肺部三级淋巴器官的形成。它还减少了调节性滤泡 T 细胞，增加了 Tfh 细胞、B 细胞、抗体亲合力和中和能力，导致受感染小鼠的抗 RSV 体液反应总体改善。用来自 IL-21 治疗的 RSV 感染小鼠的纯化免疫球蛋白 G 进行被动免疫，以防止 RSV 感染。

更新日期：2020-10-17

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