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bioRxiv · 10.1101/2025.08.15.669900

Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function

Lissner, M. M.·Sullivan, J. M.·Ni, M.·Sherve, M.·Hocking, A. M.·Hamerman, J. A.·Campbell, D. J.
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Abstract

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.

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Lissner, M. M., Sullivan, J. M., Ni, M., Sherve, M., Hocking, A. M., Hamerman, J. A., Campbell, D. J.. 2025-08-20. Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function. https://doi.org/10.1101/2025.08.15.669900

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