The production of high-affinity antibodies is a key feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. However, dysregulated production of antibodies can cause immune pathologies, such as autoimmunity and immune deficiency. Long-lived humoral immunity depends on B-cell help provided by T follicular helper (Tfh) cells, which support the differentiation of antigen (Ag)-specific B cells into memory and plasma cells. Tfh cells are generated from naïve CD4⁺ T cells following the receipt of inputs from various cell surface receptors, and can undergo further differentiation into subsets with specialised effector functions to induce and maintain serological memory. While genetically modified mice have provided great understanding of the requirements for generating Tfh cells, it is critical that requirements for human Tfh cell generation and function are also established. Key insights into the molecular requirements for human Tfh cells have been elucidated from the systematic analysis of humans with monogenic germline variants that cause inborn errors of immunity characterised by impaired humoral immunity following infection or vaccination or immune dysregulation and autoimmunity. In this review we will discuss how studying rare ‘experiments of nature’ has enabled discovery of non-redundant molecules and pathways necessary for Tfh cell generation, differentiation, regulation and function in humans, and how these findings inform us about basic and clinical immunology.

高亲和力抗体的产生是脊椎动物免疫系统的一个关键特征。抗体中和并清除病原体，从而预防传染病。然而，抗体的失调产生会导致免疫疾病，例如自身免疫和免疫缺陷。长寿命的体液免疫依赖于 T 滤泡辅助 (Tfh) 细胞提供的 B 细胞帮助，Tfh 支持抗原 (Ag) 特异性 B 细胞分化为记忆细胞和浆细胞。Tfh 细胞由幼稚 CD4 ⁺T 细胞在接受来自各种细胞表面受体的输入后，可以进一步分化成具有特殊效应功能的亚群，以诱导和维持血清学记忆。虽然转基因小鼠对生成 Tfh 细胞的要求有了很好的了解，但对人类 Tfh 细胞的生成和功能的要求也必须建立起来。对人类具有单基因种系变异的系统分析阐明了对人类 Tfh 细胞分子需求的关键见解，这些变异导致先天性免疫错误，其特征是感染或接种疫苗后体液免疫受损或免疫失调和自身免疫。