The Src family kinases Lck and Fyn promote transendothelial migration of T cells

T cells' ability to traverse endothelial barriers and infiltrate peripheral tissues is vital for the body's adaptive immune response. Integrins, like LFA-1, are key players in this process by functioning as adhesion molecules and initiating signaling pathways that facilitate cell migration. However, the specific molecular mechanisms that enable T cell migration remain largely unexplored.

This study reveals that the Src family kinases Lck and Fyn are essential for efficient T cell migration. When T cells are deficient in either Lck, Fyn, or both kinases, they show impaired random migration across surfaces coated with ICAM-1, affecting parameters such as speed and mean squared displacement. Further investigation into the signaling pathways revealed that Lck is crucial for activating the PI3K signaling downstream of LFA-1, while Fyn does not play a role in this process.

The absence of Lck disrupted the normal interaction between the PI3K regulatory subunit p85 and its tyrosine-phosphorylated binding partners, suggesting that Lck may modulate PI3K activity by controlling p85 protein-protein interactions. Crucially, both Lck and Fyn were necessary for T cell transmigration across an inflamed endothelial barrier, a critical step for tissue infiltration.

Moreover, the use of a small-molecule Lck kinase inhibitor was found to reduce PI3K signaling and T cell transmigration, indicating that Lck's kinase activity is indispensable for this process.

In summary, this research identifies a novel role for the Lck and Fyn kinases in promoting T cell transmigration, providing valuable insights into the molecular mechanisms underlying adaptive immune responses.