Nancy Hogg

Role of LFA-1 in leukocyte migration

The ability of T lymphocytes (T cells) to adhere and migrate is critical for a fully functional immune system. T cells leave the blood stream by migrating along vessel surfaces, scanning for a suitable exit point into lymph nodes or, following infection, into other tissues (reviewed in 1). They are also highly migratory within these tissues, thereby enhancing the opportunity for encounter with antigen presenting cells and other targets. Therefore, persistent migration is central to T cell function and it becomes important to understand the molecular mechanisms that underlie this motility.

T cells migrate on ICAM-1 that has widespread distribution following induction by inflammatory agents. This migratory activity comes about by signaling through the integrin LFA-1 expressed by T cells and other leukocytes. We are interested in how LFA-1 promotes both random and chemoattractant directed migration. Following binding to ICAM-1, signals through LFA-1 cause the reorganisation of the F-actin cytoskeleton and adhesion/migration is dependent upon this step². The process involves both myosin light chain kinase and also Rho kinase acting through myosin II³. More recently we have investigated the distribution of LFA-1 itself and have described a "focal zone" of clustered high affinity LFA-1 which is positioned in the mid cell region of the migrating cell⁴. This zone is the major focus of adhesion for the migrating cell, leaving the lamelli at the leading edge free to scan surfaces. The non-attached uropod at the rear of the T cell forms a third compartment. There is still much to understand of the molecular details of how an integrin like LFA-1 regulates the activities of these three regions of the migrating cell enabling migration to proceed. Projects will be available within this topic area.

We have also made use of the LFA-1 null mice to study the trafficking in vivo of leukocytes as naïve cells and following inflammation^{5 - 7}. Projects will involve investigation of mouse lymphocyte migration within lymph nodes and also in in vitro models of migration similar to the human studies.

References

1. Hogg N, et al. 2003. T cell integrins-more than just sticking points. J Cell Sci 2003; 116: 4695-4705.
2. Porter JC, et al. Signaling through integrin LFA-1 leads to filamentous actin Polymerization and remodeling, resulting in enhanced T Cell adhesion. J Immunol 2002; 168: 6330-6335.
3. Smith A, et al. LFA-1-induced migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment. J Cell Sci 2003; 116: 3123-3133.
4. Smith A, et al. A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes. J Cell Biol 2005; (in press).
5. Berlin-Rufenach C, et al. Lymphocyte migration in LFA-1 deficient mice. J Exp Med 1999; 189: 1467-78.
6. Henderson R, et al. The use of LFA-1-deficient mice to determine the role of LFA-1, Mac-1, and α4 integrin in the inflammatory response of neutrophils. J Exp Med 2001; 194: 219-236.
7. Henderson R, et al. Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood 2003; 102: 328-335.