Lissner Michelle M, Sullivan Jenna M, Ni Minjian, Sherve McKenna, Hocking Anne M, Hamerman Jessica A, Campbell Daniel J
Benaroya Research Institute; Seattle, USA.
Department of Immunology, University of Washington; Seattle, USA.
bioRxiv. 2025 Aug 20:2025.08.15.669900. doi: 10.1101/2025.08.15.669900.
T cell immunity depends on the precise coordination of signaling networks with actin cytoskeleton remodeling, yet the molecular regulators of these processes remain incompletely defined. Flightless-1 (FLII) is a gelsolin-family actin regulator with unique leucine-rich repeats that can couple cytoskeletal dynamics to diverse signaling pathways. Here, using conditional knockout mice, we identify essential roles for FLII in both CD8⁺ and regulatory T cells. Loss of FLII in CD8⁺ T cells caused a profound loss of naive cells from the spleen, impaired CCR7-dependent migration, and defective accumulation in the lung parenchyma during antigen-specific responses to respiratory vesicular stomatitis virus infection, despite largely preserved activation, effector differentiation, and cytotoxic function. FLII-deficient Foxp3⁺ regulatory T cells maintained normal numbers but exhibited diminished CD25 expression, defective IL-2 signaling, and failed to restrain spontaneous, tissue-specific autoimmunity. These findings identify FLII as a critical and previously unrecognized orchestrator of T cell trafficking and immune regulation, which may link chemokine receptor signaling to actin remodeling and is essential for proper T cell migration and function.
T细胞免疫依赖于信号网络与肌动蛋白细胞骨架重塑的精确协调，然而这些过程的分子调节因子仍未完全明确。无翅型-1（FLII）是一种凝溶胶蛋白家族的肌动蛋白调节因子，具有独特的富含亮氨酸的重复序列，能够将细胞骨架动力学与多种信号通路联系起来。在此，我们利用条件性敲除小鼠，确定了FLII在CD8⁺T细胞和调节性T细胞中的重要作用。CD8⁺T细胞中FLII的缺失导致脾脏中幼稚细胞大量减少，损害了依赖CCR7的迁移，并在针对呼吸道水泡性口炎病毒感染的抗原特异性反应期间，肺实质中的聚集存在缺陷，尽管激活、效应分化和细胞毒性功能在很大程度上得以保留。FLII缺陷的Foxp3⁺调节性T细胞数量维持正常，但CD25表达减少，IL-2信号传导存在缺陷，并且无法抑制自发性、组织特异性自身免疫。这些发现确定FLII是T细胞运输和免疫调节的关键且此前未被认识的协调因子，它可能将趋化因子受体信号传导与肌动蛋白重塑联系起来，并且对于T细胞的正常迁移和功能至关重要。
