The interleukin-8 receptor B and CXC chemokines can mediate transendothelial migration of human skin homing T cells.
We studied the involvement of chemokines that bind to G protein-coupled receptors in the migration of skin homing T cells across a bilayer vascular construct (BVC) consisting of a fibroblast matrix underneath an activated endothelial (EC) monolayer. Based on the expression of the cutaneous lymphocyte-associated antigen (CLA), a skin homing receptor, CD45R0+ T cells freshly isolated from blood or HUT-78 cutaneous T lymphoma cells were separated into CLA+ and CLA- subpopulations. These T cells were incubated on interleukin (IL)-1 beta and tumor necrosis factor-alpha-activated EC, and the number of transmigrated cells was determined. The chemokine IL-8 was selectively involved in the enhanced migration of CLA+ T cells across activated EC as demonstrated by blocking antibody to IL-8 but not to GRO-alpha, MCP-1 and RANTES. Identical results were obtained with both human umbilical vein EC (HUVEC) and microvascular skin EC (HDMEC). Pertussis toxin selectively inhibited the enhanced transendothelial migration (TEM) of CLA+ T cells, suggesting that CLA-dependent TEM depends on Gi protein-transmitted signals. Moreover, the IL-8 receptor B (IL-8RB) appeared to be functionally involved in TEM, as demonstrated by receptor desensitization with the CXC chemokines IL-8 and GRO-alpha and by blocking the IL-8RB with specific monoclonal antibodies. Although only the IL-8RB was involved in CLA-dependent TEM, mRNA encoding IL-8RA and IL-8RB was expressed by both CLA+ and CLA- T cells. This correlated with IL-8RA and IL-8RB surface expression on these cells. Thus, the IL-8RB is selectively functional in TEM of T cells expressing the skin homing receptor CLA. Our results demonstrate a critical role for IL-8 and possibly other IL-8RB ligands in addition to the IL-8RB in TEM and suggest the involvement of these molecules in the homing of specific T cells to inflamed skin.
Santamaria Babi
L F
LF
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
Moser
B
B
Perez Soler
M T
MT
Moser
R
R
Loetscher
P
P
Villiger
B
B
Blaser
K
K
Hauser
C
C
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D002465:Cell Movement; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D011817:Rabbits; D018123:Receptors, Interleukin / Q000502:physiology*; D023062:Receptors, Interleukin-8A; D012867:Skin / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology*
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C063419:CTAGE1 protein, human; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D017493:Leukocyte Common Antigens