Abstract 2110 Allergy, Immunology, and Rheumatology Poster Symposium, Sunday, 5/2

Lymphocyte circulation plays an important role in the generation of immune responses. Mature lymphocytes continuously circulate between blood and lymph, entering the lymphoid tissue via high endothelial venules (HEVs). Trafficking across HEVs of peripheral lymph nodes (PLN) depends on the expression of L-selectin. It has been shown that L-selectin is rapidly shed from the surface of the cell by an unknown metalloproteinase after in vitro activation. Here, we show that ligation of human CD4 by mAb or HIV-1 causes downregulation of L-selectine on T helper cells from human CD4 transgenic mice (huCD4tg) and normal human PBMCs, in this absence of cellular activation. This downregulation is due to shedding, since it is reversed by the addition of hydroxamic acid-based metalloproteinase inhibitors, and levels of soluble L-selectin (sL-selectin) are increased in sera of mice treated with anti-CD4 mAb. We show that in vivo downregulation of L-selectin in human CD4 transgenic (huCD4tg) mice by mAb reduces homing of lymphocytes to PLN in adoptive transfer experiments. This downregulation of L-selectin induced by CD4 ligation could play a role in the pathogenesis of AIDS. Crosslinking CD4 with viral gp120 and subsequent downregulation of L-selectin might contribute to immune deficiency in HIV infected individuals by inhibiting T cell redistribution and decreasing the probability of an encounter between specific lymphocytes and viral antigens in PLN.