MEK signalling tunes actin treadmilling for interstitial lymphocyte migration

Abstract

Lymphocytes must undergo various modes of migration during an immune response, depending on the underlying substrate. The identification of a signalling module required specifically for 3D motility sheds light onto how these different migratory mechanisms can be regulated.

Figure 1

A Ras–MEK–cofilin module exclusively regulates 3D T-cell migration. Schematic views of 3D versus 2D migration modes of T lymphocytes. Shown are side views of a T lymphocyte migrating in 3D interstitial space (top) or on a flat 2D surface such as an endothelial lining (bottom). The direction of movement is indicated by an arrow. During 3D migration, T cells make multiple protrusions at the leading edge and ‘slide' through the narrow interstitial pores. Binding of the chemokine SDF-1 to CXCR4 triggers Ras activation via Gαi and this in turn leads to MEK-dependent cofilin dephosphorylation. Migration in 3D is mainly driven by actin polymerization and therefore the localized severing and depolymerizing activity of dephosphorylated cofilin is critical to initiate cellular protrusions. Chemokine-induced T-cell migration on 2D surfaces on the other hand is guided by an interplay of adhesion and contraction, resulting in a ‘walking' mode that requires Ras, but not necessarily MEK activation and cofilin dephosphorylation.