The Role of E-Selectin, P-Selectin, and Very Late Activation Antigen-4 in T Lymphocyte Migration to Dermal Inflammation

Abstract

T lymphocyte infiltration into inflamed tissues is thought to involve lymphocyte rolling on vascular endothelial cells. Because both selectin and α4 integrin adhesion molecules can mediate leukocyte rolling, the contribution of these receptors to lymphocyte migration to inflammation was examined. The recruitment of 111In-labeled spleen T cells to intradermal sites injected with IFN-γ, TNF-α, LPS, poly inosine-cytosine, and Con A was measured in the rat, and the effect of blocking mAbs to E-selectin, P-selectin, very late activation Ag-4 (VLA-4), and LFA-1 was determined on this T cell migration in vivo. Anti-E-selectin and anti-P-selectin mAbs each inhibited 10–40 and 20–48%, respectively, of the T lymphocyte migration to the inflammatory sites, depending on the stimulus. Blocking VLA-4 inhibited 50% of the migration to all of the lesions except Con A. Treatment with both anti-VLA-4 and anti-E-selectin mAbs inhibited up to 85% of the lymphocyte accumulation, while P-selectin and VLA-4 blockade in combination was not more effective than VLA-4 blockade alone in TNF-α, IFN-γ, LPS, and poly inosine-cytosine lesions. Inhibiting E-selectin, P-selectin, and VLA-4 together nearly abolished lymphocyte migration to all inflammatory sites. Anti-LFA-1 mAb strongly inhibited lymphocyte accumulation by itself, and this inhibition was not significantly further reduced by E- or P-selectin blockade. Thus, T cell migration to dermal inflammation is dependent on E-selectin, P-selectin, and VLA-4, likely because these three receptors are required for rolling of memory T lymphocytes, but VLA-4 and E-selectin are especially important for lymphocyte infiltration in these tissues.

CXCR3 is required for migration to dermal inflammation by normal andin vivo activated T cells: differential requirements by CD4 and CD8 memory subsets

“…Previously we have shown that blockade of either Eselectin alone or a 4 b 1 alone could partially inhibit T cell migration to inflamed skin, and combined blockade inhibited most of this T cell recruitment [25]. This suggested that a 4 b 1 vascular cell adhesion molecule-1 binding was required for part of this migration, but that the accumulation was also mediated through E-selectin-CLA interactions.…”

Role of α4 integrin and its ligand VCAM‐1 in the specific extravasation of a tumor‐specific TH2 clone into tumor tissue that initiates its rejection

“…In general, there appear to be various different pathways responsible for T-cell migration mechanisms. 6,9,[37][38][39] Several investigators have reported that T-cell migration from blood vessels into the extravascular matrix involves adhesion between integrin ␣4␤1 molecules on T cells and VCAM-1 molecules on vascular endothelial cells. 29,40,41 Moreover, in vitro adhesion of integrin ␣4␤1 on human T cells to VCAM-1 can be nonspecifically upregulated by a chemokine, MIP-1␤.…”

T Cell Requirement for Development of Chronic Ulcerative Dermatitis in E- and P-Selectin-Deficient Mice

“…Blockade of both E-and P-selectin and ␣ 4 integrin function severely impaired lymphocyte recruitment in these models of dermal inflammation (Ͼ90%; Ref. 16). Although E-and P-selectin have a role in lymphocyte recruitment, they are not strictly required in some models of inflammation.…”