Department of Medical Oncology and Hematology, University of Zürich and University Hospital Zürich, Zürich, Switzerland.
Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland.
Front Immunol. 2021 Sep 9;12:716405. doi: 10.3389/fimmu.2021.716405. eCollection 2021.
Naïve T cells (T) constitutively recirculate through secondary lymphatic organs (SLOs), where they scan dendritic cells (DCs) for cognate peptide-loaded major histocompatibility complexes (pMHC). Continuous trafficking between SLOs not only enables rapid clonal selection but also ensures T homeostasis by providing access to prosurvival signals from TCR, IL-7R, and the chemokine receptor CCR7. Inside the lymphoid tissue, CCR7-mediated T motility is mainly driven by the Rac activator DOCK2, with a separate contribution by a phosphoinositide-3-kinase γ (PI3Kγ)-dependent pathway. Tec tyrosine kinases and the Rac activator Tiam1 constitute prominent downstream effectors of PI3K signaling. Yet, the precise role of Tec kinase versus Tiam1 signaling during CCR7-mediated T migration and homeostasis remains incompletely understood. Here, we examined the function of the Tec family member interleukin-2-inducible T-cell kinase (Itk) and Tiam1 during T migration and using intravital microscopy. Itk deficiency caused a mild decrease in CCR7-triggered T migration, mirroring observations made with PI3Kγ; T cells, while lack of Tiam1 did not affect T motility. modeling suggested that reduced migration in the absence of Itk does not result in a substantial decrease in the frequency of T encounters with DCs within the lymphoid tissue. In contrast, Itk was important to maintain homeostasis of CD4 T, also in MHCII-deficient hosts. Taken together, our data suggest that Itk contributes to T migration and survival by integrating chemokine receptor and TCR signaling pathways.
幼稚 T 细胞 (T) 持续循环通过次级淋巴器官 (SLO)，在那里它们扫描树突状细胞 (DC) 以寻找同源肽负载的主要组织相容性复合物 (pMHC)。SLO 之间的连续运输不仅能够实现快速克隆选择，还通过提供来自 TCR、IL-7R 和趋化因子受体 CCR7 的生存信号来确保 T 细胞的稳态。在淋巴组织内，CCR7 介导的 T 细胞迁移主要由 Rac 激活剂 DOCK2 驱动，而磷酸肌醇 3-激酶 γ (PI3Kγ) 依赖性途径也有独立的贡献。 Tec 酪氨酸激酶和 Rac 激活剂 Tiam1 是 PI3K 信号的突出下游效应子。然而，在 CCR7 介导的 T 细胞迁移和稳态过程中 Tec 激酶与 Tiam1 信号的精确作用仍不完全清楚。在这里，我们使用活体显微镜检查了 Tec 家族成员白细胞介素 2 诱导的 T 细胞激酶 (Itk) 和 Tiam1 在 T 细胞迁移和稳态中的功能。Itk 缺陷导致 CCR7 触发的 T 细胞迁移轻度减少，与观察到的 PI3Kγ 结果相似；缺乏 Tiam1 的 T 细胞迁移没有受到影响。建模表明，Itk 缺乏不会导致 T 细胞在淋巴组织内与 DC 相遇的频率显著降低。相比之下，Itk 对于 CD4 T 细胞的稳态也很重要，即使在 MHCII 缺陷型宿主中也是如此。综上所述，我们的数据表明，Itk 通过整合趋化因子受体和 TCR 信号通路来促进 T 细胞迁移和存活。
