Chemokine independent T cell migration

Our current understanding of T cell migration is focused on chemokine-mediated integrin activation, which dictates that chemokines provide critical directional signals to guide T cell migration to target tissues within the body. Emerging evidence, however, supports that activated T cells can migrate to certain vascularized tissues, despite chemokine receptor deficiency or with the inhibition of chemokine receptors. This suggests the presence of a chemokine-independent mechanism through which T cells can activate integrins, induce adhesion and subsequent cell migration. We found with OT-I T cell receptor transgenic mice that integrin LFA-1 mediated migration of naive T cells was strictly dependent on chemokine stimulation. In contrast, activated CD8 + T cells migrated in the absence of chemokines both in vitro and in vivo. Additionally, activated CD8 + T cells migrate in the presence of the chemokine inhibitors pertussis toxin and Gallein (a Gβγ inhibitor), further supporting chemokine-independent T cell migration. Using mass spectrometry, we discovered three cytoskeletal molecules, non-muscle myosin heavy chain IIA (MyH9), αII-spectrin, and βII-spectrin, associate with LFA-1 in T cells. Western blot analysis of mouse T cells revealed expression levels of MyH9 and αII-spectrin remained stable after T cell activation, but surprisingly, βII-spectrin expression was dramatically down-regulated during CD8 + T cell activation. Over-expression of βII-spectrin in activated CD8 + T cells abolished chemokine-independent migration on integrin ligand ICAM-1. Therefore, we hypothesize that βII-spectrin provides a mechanical link between LFA-1 and the cytoskeleton to regulate T cell migration without chemokine stimulation.