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.

CD4 ⁺ T 辅助细胞 22 (Th22) 细胞是一种表型不同的淋巴细胞亚群，可产生高水平的白细胞介素 (IL)-22，而不会同时产生 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。更好地理解支持 Th22 细胞生长的机制将有助于深入了解它们在稳态、感染和疾病期间的调节。为了解决这一知识差距，我们生成了“IL-17A-命运映射 IL-17A/IL-22 报告基因转基因小鼠”，并表明 Th22 细胞在细菌感染期间在胃肠道和肺部发育而不通过Il17a转变-表达中间体，尽管在某些隔间中存在替代的过渡途径。Th22 细胞的发育不依赖于 T-bet；然而，该转录因子除了调节 Th22 细胞的生长、表型稳定性和可塑性外，还充当 IL-17A 和 IL-22 产生的混杂 T 细胞内在调节因子。因此，我们证明在粘膜细菌感染部位，Th22 细胞发展为独立于 Th17 细胞的独特谱系；尽管这两个谱系在受感染组织及其引流淋巴结内都表现出双向表型灵活性，并且 T-bet 在 Th22 细胞功能和特性中起着关键的调节作用。