Formin-like-1 mediates effector T cell extravasation through restrictive endothelial barriers enabling T cell entry into peripheral tissues and autoimmunity induction

Autor: Jordan Jacobelli, Scott B. Thompson, Adam M. Sandor, Victor Lui, Jeffrey W. Chung, Monique M. Waldman, Rachel S. Friedman
Rok vydání: 2020
Předmět:
Zdroj: The Journal of Immunology. 204:220.12-220.12
ISSN: 1550-6606
0022-1767
Popis: To perform their functions, T cells migrate from the blood vasculature into tissues by traversing the vascular wall through a process known as transendothelial migration (TEM). While many of the extracellular cues that guide this process have been identified, the role of downstream cytoskeletal effectors that mediate force generation and morphological changes required for TEM remains an area of active research. Formin-like-1 (FMNL1) is a cytoskeletal effector that mediates cytoskeletal remodeling. However, the role of FMNL1 in T cell functions, and migration in particular, is mostly unknown. The goal of our study was to examine the role of FMNL1 in T cell extravasation and trafficking. We generated a new FMNL1 knock-out (KO) mouse and identified a novel role for FMNL1 in promoting T cell migration through restrictive endothelial barriers during TEM. In vitro, FMNL1-deficient T cells had reduced actin polymerization in response to chemokine signaling. Furthermore, FMNL1 KO T cells had a selective impairment in chemotaxis through restrictive 3μm pores vs permissive 5μm pores. Using time-lapse microscopy, we determined that FMNL1-deficient T cells are severely impaired in their capacity to complete TEM through endothelial barriers. In vivo, we found that FMNL1 was dispensable for T cell extravasation through permissive high endothelial venules and homeostatic trafficking to lymphoid organs. Instead, FMNL1 regulated the ability of activated T cells to extravasate into inflamed peripheral tissues and enabled self-reactive T cells to induce autoimmune disease. Overall, our data identify FMNL1 as a key regulator of lymphocyte migration through restrictive barriers and as a potential target for modulating effector T cell trafficking.
Databáze: OpenAIRE
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