Hocking, A. M. | bioRxiv Science

bioRxiv2025

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

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.

immunology↗

bioRxiv2020

The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity

Despite a rapidly growing body of literature on COVID-19, our understanding of the immune correlates of disease severity, course and outcome remains poor. Using mass cytometry, we assessed the immune landscape in longitudinal whole blood specimens from 59 patients presenting with acute COVID-19, and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls. We found that the immune landscape in COVID-19 forms three dominant clusters, which correlate with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who have a moderate disease course, whereas those with severe disease have features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade. The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.

immunology↗