Kim Hans, Chan Amanda, Vimopatranon Sinmanus, Girard Alexandre, Jiang Andrew, Wertz Samuel, Hwang Il-Young, Kehrl John H, Schmeisser Hana, Seemiller Madelyn M, Lusso Paolo, Huang Dawei, Wei Danlan, Goes Livia R, Soares Marcelo, Martinelli Elena, Arthos James, Cicala Claudia
bioRxiv. 2025 Jun 27:2025.06.23.660664. doi: 10.1101/2025.06.23.660664.
Tissue resident memory CD4 T cells (T s) populate mucosal sites and play a critical role in local immune responses. Gut T cells persist for extended periods in the gut mucosa where they rapidly respond to invading pathogens and provide long lasting protection. This study investigates the factors that mediate differentiation of naïve CD4 T cells into cells presenting a gut T phenotype. Naïve CD4 T cells were cultured under conditions that mimicked mucosal environments. This included signaling through MAdCAM-1 in the presence of Retinoic Acid (RA) and TGF-β. This combination of stimuli primed naïve CD4 T cells to adopt a T phenotype. However, to fully differentiate into T s an additional soluble factor provided by memory T cells was required. Our results identified IL-6 as a key factor that induces the expression of T -associated markers, including CD69, CD103 and CCR5. This unique combination of stimuli promoted T differentiation despite low level proliferation. T differentiation was mediated through JAK/STAT signaling, and antagonists that target JAK/STAT pathways suppressed MAdCAM-1 mediated T cell formation. Our findings revealed that MAdCAM-1 works together with TGF-β, RA and IL-6 in this process. Such information may aid in the design of next generation adjuvants and effective mucosal vaccines. Additionally, each of these factors may be targeted to treat excessive gut inflammation associated with conditions like inflammatory bowel disease. Overall, these findings provide new strategies aimed at modulating immune responses to invading pathogens and identify therapeutic approaches toward regulating gut inflammation.
Immunologists and vaccinologists have long been interested in strategies aimed at boosting immune responses in mucosal tissues where pathogens are first encountered. Gut Tissue resident memory T cells (T s) play a central role in gut homeostasis and immunity. They provide a rapid long-lasting protection against pathogens. T s must target harmful pathogens and at the same time tolerate harmless commensal bacteria. This balance between immunity and tolerance in the complex environment of gut tissues is essential to the maintenance of gut homeostasis. In this study we have identified key factors present in the gut tissue milieu that are involved in T differentiation from naïve T cells. These findings point to new therapeutic approaches that can potentially target immune responses in gut tissues and may help in developing effective mucosal vaccines. Conversely, these factors may be targeted in excessive gut inflammation involved in conditions like inflammatory bowel disease (IBD).
组织驻留记忆CD4 + T细胞（Trm细胞）聚集在黏膜部位，在局部免疫反应中起关键作用。肠道Trm细胞在肠道黏膜中长期存在，在那里它们能迅速对入侵病原体作出反应并提供持久保护。本研究调查了介导初始CD4 + T细胞分化为具有肠道Trm细胞表型细胞的因素。将初始CD4 + T细胞在模拟黏膜环境的条件下培养。这包括在视黄酸（RA）和转化生长因子-β（TGF-β）存在的情况下通过黏膜地址素细胞黏附分子-1（MAdCAM-1）进行信号传导。这种刺激组合使初始CD4 + T细胞准备好采用Trm细胞表型。然而，要完全分化为Trm细胞，还需要记忆T细胞提供的另一种可溶性因子。我们的结果确定白细胞介素-6（IL-6）是诱导包括CD69、CD103和CC趋化因子受体5（CCR5）在内的Trm细胞相关标志物表达的关键因子。尽管增殖水平较低，但这种独特的刺激组合促进了Trm细胞分化。Trm细胞分化是通过JAK/STAT信号传导介导的，靶向JAK/STAT途径的拮抗剂抑制了MAdCAM-1介导的T细胞形成。我们的研究结果表明，在这个过程中MAdCAM-1与TGF-β、RA和IL-6共同发挥作用。这些信息可能有助于设计下一代佐剂和有效的黏膜疫苗。此外，这些因素中的每一个都可能成为治疗与炎症性肠病等病症相关的过度肠道炎症的靶点。
免疫学家和疫苗学家长期以来一直对旨在增强在首次遇到病原体的黏膜组织中的免疫反应的策略感兴趣。肠道组织驻留记忆T细胞（Trm细胞）在肠道稳态和免疫中起核心作用。它们为抵御病原体提供快速持久的保护。Trm细胞必须靶向有害病原体，同时耐受无害的共生细菌。在肠道组织的复杂环境中，免疫与耐受之间的这种平衡对于维持肠道稳态至关重要。在本研究中，我们确定了肠道组织环境中参与从初始T细胞分化为Trm细胞的关键因素。这些发现指向了新的治疗方法，这些方法可能潜在地靶向肠道组织中的免疫反应，并可能有助于开发有效的黏膜疫苗。相反，在炎症性肠病（IBD）等病症中涉及的过度肠道炎症中，这些因素可能成为靶点。
