Abstract
Chemokines promote T cell migration by transmitting signals that induce T cell polarization and integrin activation and adhesion. Mst1 kinase is a key signal mediator required for both of these processes; however, its molecular mechanism remains unclear. Here, we present a mouse model in which Mst1 function is disrupted by a hypomorphic mutation. Microscopic analysis of Mst1-deficient CD4 T cells revealed a necessary role for Mst1 in controlling the localization and activity of Myosin IIa, a molecular motor that moves along actin filaments. Using affinity specific LFA-1 antibodies, we identified a requirement for Myosin IIa-dependent contraction in the precise spatial distribution of low and higher affinity LFA-1 on the membrane of migrating T cells. Mst1 deficiency or Myosin inhibition resulted in multipolar cells, difficulties in uropod detachment and mis-localization of low affinity LFA-1. Thus, Mst1 regulates Myosin IIa dynamics to organize high and low affinity LFA-1 to the anterior and posterior membrane during T cell migration.
Highlights
Human mutations in the Mst1 gene result in a primary immunodeficiency disease [1,2,3]
WeeT mice were outcrossed to 129Sv/ImJ mice and F2 progeny were used to map the causative mutation by correlating phenotype and inheritance of C57BL/6 (B), 129Sv/ImJ (C) or both (H, heterozygous) single nucleotide polymorphisms (SNPs) using a Single nucleotide polymorphism (SNP) panel [31,35]
ICAM-1 was unable to promote CCL19-induced migration through 3 mm pores compared to chemokine-free, ICAM-1 only controls (Fig. 3C). These findings indicate that LFA-1 outside-in signaling can partially compensate for Mst1 deficiency in promoting T cell migration through non-constraining pores; there is a strict requirement for Mst1 in T cell migration that requires cellular contractility
Summary
Human mutations in the Mst gene result in a primary immunodeficiency disease [1,2,3]. Naıve and central memory T cells traffic between the blood and lymphatics. They patrol secondary lymphoid organs such as the spleen and lymph nodes for cognate antigen brought there by tissue-derived antigen presenting cells. T cell trafficking patterns are programmed by the expression of membrane chemokine receptors and adhesion molecules, including selectins and integrins [9]. T cells enter secondary lymphoid organs and peripheral tissue from the vasculature by extravasation. Naıve and central memory T cells are guided by the chemokines CCL19 and CCL21 to migrate along fibroblastic reticular cells in an integrin-independent manner. Effector T cells are recruited to sites of infection by chemotactic cues and extravasate in an integrin-dependent manner. Migration of effector T cells within the inflamed tissue is highly dependent on integrins and is completely disrupted by integrin blocking antibodies [10]
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