Metabolic hormone leptin promotes the function of TFH cells and associates with vaccine responses
Metabolic hormone leptin promotes the function of TFH cells and associates with vaccine responses
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代谢激素瘦素促进 TFH 细胞的功能并与疫苗反应相关
DOI：
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发表时间：
2021
影响因子：
16.6
通讯作者：
Wim Pierson
中科院分区：
文献类型：
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作者：
Jun Deng;Qian Chen;Zhian Chen;Kaili Liang;Xin Gao;Xiaohui Wang;Fadzai V Makota;Hong Sheng Ong;Yanmin Wan;Kaiming Luo;Dongcheng Gong;Xiang Yu;Sarina Camuglia;Qunxiong Zeng;Tao Zhou;Feng Xue;Jing He;Yunbo Wei;Fan Xiao;Jianyang Ma;Danika L. Hill;Wim Pierson
滤泡辅助T细胞是一种特殊的CD4+ T细胞亚群，通过支持抗体亲和成熟和记忆形成来关键控制抗体反应。ICOS、SH2D1A（编码SAP）、IL12RB1、IL21R和STAT3的基因突变导致免疫缺陷和T - FH生成受损，而自身抗原和促炎细胞因子的持续刺激在自身免疫性疾病中驱动过度的T - FH分化。尽管对T FH细胞在疾病中的作用有重要的了解，但在健康个体中调节T FH细胞功能的机制却很少。在没有这些知识的情况下，我们很难理解为什么很大一部分普通人群对某些疫苗反应无效，因为T - FH活性被认为是疫苗反应的关键限制因素。在这里，我们报告了代谢激素瘦素不足与普通人群对流感和乙型肝炎病毒（HBV）疫苗反应降低之间的关联。我们发现瘦素促进小鼠和人的T - FH分化和IL-21的产生，这是由STAT3和mTOR途径介导的。小鼠瘦素信号的遗传缺陷不仅损害了T - FH的产生和抗体反应，在禁食条件下诱导的小鼠瘦素限制瘫痪了流感疫苗介导的对随后感染挑战的保护，这在很大程度上是通过瘦素替代来恢复的。我们的研究结果确定瘦素是T - FH细胞的天然调节剂和疫苗效力的潜在生物标志物。
Follicular helper T (T FH ) cells are a specialised CD4+ T cell subset that critically controls antibody responses by supporting antibody affinity maturation and memory formation.Genetic mutations in ICOS, SH2D1A (encoding SAP), IL12RB1, IL21R and STAT3 result in immunodeficiency with impaired T FH generation, whereas continuous stimulations from autoantigens and pro-inflammatory cytokines drive excessive T FH differentiation in autoimmune diseases. Despite significant knowledge of T FH cells in diseases, the mechanisms underlying the regulation of T FH cell function in healthy individuals are scarce. Without such knowledge, we poorly understand why a significant portion of the general population respond ineffectively to certain vaccines, because T FH activity is considered as the key limiting factor for vaccine responses. Here, we report an association between insufficient metabolic hormone leptin and reduced vaccine responses of the general population to influenza and hepatitis B virus (HBV) vaccines. We revealed that leptin promotes both mouse and human T FH differentiation and IL-21 production, which are mediated by STAT3 and mTOR pathways. Not only did the genetic deficiency of leptin signalling in mice impair T FH generation and antibody responses, the leptin restriction in mice that were induced by fasting conditions paralysed influenza vaccination-mediated protection for the subsequent infection challenge, which was largely rescued by leptin replacement. Our results identify leptin as a natural regulator of T FH cells and a potential biomarker for vaccine efficacy.