T-helper 22 cells develop as a distinct lineage from Th17 cells during bacterial infection and phenotypic stability is regulated by T-bet
T-helper 22 cells develop as a distinct lineage from Th17 cells during bacterial infection and phenotypic stability is regulated by T-bet
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DOI：
10.1038/s41385-021-00414-6
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发表时间：
2021-06-03
影响因子：
8
通讯作者：
Foster, Paul S.
中科院分区：
文献类型：
--
作者：
Barnes, Jessica L.;Plank, Maximilian W.;Foster, Paul S.
CD4(+) t -辅助性22 （Th22）细胞是一种表型独特的淋巴细胞亚群，其产生高水平的白细胞介素(IL)-22，而不协同产生IL- 17a。然而，Th22细胞的发育起源和谱系分类、它们与Th17细胞的相互关系以及感染和炎症部位的可塑性潜力在很大程度上仍未明确。对Th22细胞生长机制的进一步了解将有助于深入了解其在体内平衡、感染和疾病过程中的调控。为了解决这一知识差距，我们产生了“IL-17A命运定位IL-17A/IL-22报告基因转基因小鼠”，并表明在细菌感染期间，Th22细胞在胃肠道和肺部发育，而不通过表达IL-17A的中间体过渡，尽管在某些区室中存在替代的过渡途径。th22细胞的发育不依赖于T-bet；然而，除了调节Th22细胞的生长、表型稳定性和可塑性外，该转录因子还作为IL-17A和IL-22产生的混杂t细胞内在调节剂发挥作用。因此，我们证明在粘膜细菌感染的部位，Th22细胞独立于Th17细胞发展为一个独特的谱系；尽管这两种谱系在感染组织及其引流淋巴结中都表现出双向表型灵活性，并且T-bet在th22细胞功能和身份中起着关键的调节作用。
CD4(+) T-helper 22 (Th22) cells are a phenotypically distinct lymphocyte subset that produces high levels of interleukin (IL)-22 without co-production of IL-17A. However, the developmental origin and lineage classification of Th22 cells, their interrelationship to Th17 cells, and potential for plasticity at sites of infection and inflammation remain largely undefined. An improved understanding of the mechanisms underpinning the outgrowth of Th22 cells will provide insights into their regulation during homeostasis, infection, and disease. To address this knowledge gap we generated 'IL-17A-fate-mapping IL-17A/IL-22 reporter transgenic mice' and show that Th22 cells develop in the gastrointestinal tract and lung during bacterial infection without transitioning via an Il17a-expressing intermediate, although in some compartments alternative transition pathways exist. Th22-cell development was not dependent on T-bet; however, this transcription factor functioned as a promiscuous T-cell-intrinsic regulator of IL-17A and IL-22 production, in addition to regulating the outgrowth, phenotypic stability, and plasticity of Th22 cells. Thus, we demonstrate that at sites of mucosal bacterial infection Th22 cells develop as a distinct lineage independently of Th17 cells; though both lineages exhibit bidirectional phenotypic flexibility within infected tissues and their draining lymph nodes, and that T-bet plays a critical regulatory role in Th22-cell function and identity.