Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity
Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity
复制标题
DOI：
10.1126/sciimmunol.aay5552
复制
发表时间：
2020-03-01
影响因子：
24.8
通讯作者：
King, Carolyn G.
中科院分区：
文献类型：
--
作者：
Kuenzli, Marco;Schreiner, David;King, Carolyn G.
CD4+记忆T细胞在保护性免疫中发挥重要作用，是疫苗开发的关键靶点。许多研究都集中在T中枢记忆（T-cm）细胞上，而长寿的T滤泡辅助细胞（T-fh）的存在及其功能意义存在争议。在这里，我们发现T-fh细胞在组织分离过程中对nad诱导的细胞死亡（NICD）高度敏感，导致它们在先前的研究中代表性不足。NICD阻断表明，在感染后至少400天内，大量T-fh细胞持续高表达T-fh标记物，此时T-cm细胞已不复存在。利用单细胞RNA-seq，我们证明了长寿的T-fh细胞在转录上与T-cm细胞不同，保持了干细胞性和自我更新基因表达，并且与T-cm细胞相比，在回忆后具有多能性。在蛋白水平上，我们发现叶酸受体4 （FR4）可以区分长寿的T-fh细胞和T-cm细胞。出乎意料的是，长寿的T-fh细胞同时表达一种独特的糖酵解特征，类似于训练过的免疫细胞，包括mTOR-、HIF-1-和camp调节基因的表达升高。糖酵解/ICOS信号的晚期中断导致T-fh细胞耗损，同时脾脏浆细胞和循环抗体滴度下降，这表明T-fh的独特稳态调节及其在免疫反应记忆阶段的持续功能。这些结果突出了不同的长寿T细胞亚群的代谢异质性，并确立了T-fh细胞作为诱导持久适应性免疫的有吸引力的靶标。
CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (T-cm) cells, whereas the existence and functional significance of long-lived T follicular helper (T-fh) cells are controversial. Here, we show that T-fh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their under-representation in prior studies. NICD blockade reveals the persistence of abundant T-fh cells with high expression of hallmark T-fh markers to at least 400 days after infection, by which time T-cm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T-fh cells are transcriptionally distinct from T-cm cells, maintain stemness and self-renewal gene expression, and, in contrast to T-cm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T-fh cells from T-cm cells. Unexpectedly, long-lived T-fh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to T-fh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T-fh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish T-fh cells as an attractive target for the induction of durable adaptive immunity.