Abstract
Lymphocyte migration is essential for the function of the adaptive immune system, and regulation of T cell entry into tissues is an effective therapy in autoimmune diseases. Little is known about the specific role of cytoskeletal effectors that mediate mechanical forces and morphological changes essential for migration in complex environments. We developed a new Formin-like-1 (FMNL1) knock-out mouse model and determined that the cytoskeletal effector FMNL1 is selectively required for effector T cell trafficking to inflamed tissues, without affecting naïve T cell entry into secondary lymphoid organs. Here, we identify a FMNL1-dependent mechanism of actin polymerization at the back of the cell that enables migration of the rigid lymphocyte nucleus through restrictive barriers. Furthermore, FMNL1-deficiency impairs the ability of self-reactive effector T cells to induce autoimmune disease. Overall, our data suggest that FMNL1 may be a potential therapeutic target to specifically modulate T cell trafficking to inflammatory sites.
Highlights
T cell trafficking and extravasation into tissues are required for proper immune surveillance and execution of effector functions against pathogens and malignant cells (Masopust and Schenkel, 2013)
We examined whether FMNL1 deficiency altered the number and frequency of major immune cell populations in the thymus, blood and secondary lymphoid organs
Having seen equivalent FMNL1 KO T cell numbers in secondary lymphoid organs, we investigated whether FMNL1 deficiency affected activated T cell trafficking to sites of inflammation
Summary
T cell trafficking and extravasation into tissues are required for proper immune surveillance and execution of effector functions against pathogens and malignant cells (Masopust and Schenkel, 2013). We have recently shown that Ena/VASP proteins modulate a4 integrin expression and function in T cells to promote diapedesis (Estin et al, 2017). Investigating the mechanism of the trafficking defect, we determined that FMNL1 deficiency impairs T cell TEM at the diapedesis step due to impaired actin network remodeling and transmigration of the nucleus across endothelial barriers. We determined that FMNL1 mediates actin polymerization at the back of the T cell to promote nucleus squeezing through confined environments and that the amount of lymphocyte migration through these barriers is dictated by the level of FMNL1 expression. Our data identify FMNL1 as a novel mediator of T cell trafficking and transmigration across restrictive endothelial barriers and a regulator of self-reactive T cell autoimmunity
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