CD44-dependent hyaluronan-binding and T-lymphocyte migration

CD44 has been suggested to play a role in adhesive interactions mediating migration and extravasation of T cells into the tissues. This mediation is believed to occur as a result of CD44 binding to hyaluronic acid (HA) on the surface of endothelium. Among factors suggested to regulate this binding is the pro-inflammatory cytokine TNFα, which has been suggested to upregulate HA-binding through sulfation of the CD44 molecule. One of the objectives of this research proposal was aimed at determining the role of T cell activation, TNFα and TNFα receptors in HA binding by T lymphocytes. It was found that only highly activated T cells, which are the largest in cell size and expressed the highest levels of CD44 were the most efficient HA binders. TNFα exerts its effect on HA binding by regulating T cell activation. It increases HA binding under conditions where the cells were not optimally activated. The effects of TNFR1 (p55) and TNFR2 (p75) on HA binding can also be explained by their role in T cell activation. Thus, p55, which is not required for optimal T cell activation, has no effect on HA binding by anti-CD3 activated CD8 T cells. By contrast, p75[sub +/-] CD8 T cells, which were less optimally activated by anti-CD3 stimulation, bind much less HA than similarly activated wild type cells. The role of CD44 in migration of T lymphocytes in vivo was also determined. Various in vivo assays were used to determine whether CD44 was required for migration of polarized TH1 and TH2 cells into sites of inflammation and whether this migration correlated with HA binding. The role of CD44 in the migration of antigen-specific CD8 T cells at various times after antigen activation into lymphoid and non-lymphoid tissues was also determined. All these assays failed to demonstrate an essential role for CD44 in T cell migration. Thus, alternative mechanisms other than those mediated by CD44 are likely responsible for regulating T cell migration in vivo.Medicine, Faculty ofMedical Genetics, Department ofGraduat