Live images of LFA-1 in T cells migrating over CCL21, after initial T-cell exposure to the immobilized chemokine.

From Nat. Immunol.8, 1076-1085 (2007).

T lymphocytes migrate from the circulatory system to specialized T-cell zones in lymph nodes where they roam in search of foreign antigens. Chemokines are known to regulate lymphocyte motility, but the contribution of integrins to this process has remained elusive. In Nature Immunology, Alon and colleagues report that immobilized chemokines promote T-cell locomotion in an integrin-independent manner, and that integrin adhesiveness is regulated by mechanical signals such as shear stress.

Alon and colleagues clarified the function of chemokines and integrins in lymphocyte locomotion by tracking cell motility in vitro on a series of model surfaces decorated with the homeostatic chemokine CCL21, as well as the integrin ligands ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell-adhesion molecule-1), expressed by endothelial as well as immune and stromal cells within lymph nodes. Surface-bound - but not soluble - CCL21 alone was sufficient to trigger robust and random T-cell motility, which was not altered by integrin blockade.

In lymphocytes migrating on immobilized CCL21, the integrins LFA-1 (lymphocyte function-associated antigen-1, also known as ₁₂-integrin) and VLA-4 (very late antigen-4) clustered in the pseudopodia and uropod, respectively. To test integrin adhesiveness, beads coated with the ligands ICAM-1 or VCAM-1 were added to the medium. Surprisingly, binding to the beads was unaltered by blocking either LFA-1 or VLA-4. Likewise, integrins on T cells encountering integrin ligands and co-immobilized CCL21 failed to stop or slow down the lymphocytes migrating on the integrin ligands. Therefore, despite being polarized, integrins lack adhesiveness even when T cells encounter CCL21 and the integrin ligand together.

When continuous shear stress was applied to T lymphocytes bound to identical substrates, the authors observed that CCL21 triggered LFA-1-mediated adhesive interactions with ICAM-1. Similarly, VLA-4 was activated under shear stress conditions. Thus, in the presence of motility-promoting signals such as CCL21, LFA-1 and VLA-4 integrins can be either activated or remain 'silent', depending on the presence or absence of shear forces.

The authors transferred either wild-type (WT) or 2-integrin^-/- T cells (lacking LFA-1) into WT and ICAM-1-deficient mice and then assessed their motility within the T-cell zones of lymph nodes explanted from the recipient mice. The mutant T cells migrated in a similar manner to WT cells in both WT and ICAM-1-deficient mice, indicating that integrins do not support stable adhesion to neighbouring cells in vivo.

Taken together, these studies show that surface-bound chemokines trigger T-cell locomotion regardless of the presence of any additional adhesive ligands, and that the ability of chemokines to activate integrin adhesiveness is tightly regulated by mechanical signals. These results add to previously suggested models stating that the application of external force accelerates ligand-induced integrin transition to a high-affinity binding state. In terms of physiology, this mechanism may serve to reduce integrin activation in lymph node interstitial spaces, thus optimizing motility and preventing clumping of lymphocytes in a dense network of immune and stromal cells, which express integrin ligands and T-cell activating chemokines. Conversely, the shear flow of blood vessels may stimulate firm integrin-mediated adhesion of lymphocytes to integrin ligands and chemokines expressed on lymph node endothelial cells, a mechanism required for lymphocyte extravasation.

Author: Kim Baumann