ALPHA(4) INTEGRIN DIRECTS VIRUS-ACTIVATED CD8(-CELLS TO SITES OF INFECTION() T)

This article examines the role of VLA-4 in directing lymphocytes to si tes of viral infection using the murine lymphocytic choriomeningitis v irus infection (LCMV) as the model system. This virus by itself induce s little or no inflammation, but in most mouse/virus strain combinatio ns a potent T cell response is induced, which is associated with marke d CD8(+) cell-mediated inflammation. Two expressions of LCMV-induced i nflammation were studied: meningitis induced by intracerebral infectio n and adoptive transfer of virus-specific delayed-type hypersensitivit y. Our previous studies have shown that LCMV infection results in the appearance of activated CD8(+) cells with an increased expression of V LA-4. In this study we have compared various T cell high and low respo nder situations, and these experiments revealed that acute inflammatio n correlates directly with VLA-4 expression on splenic CD8(+) cells. T his correlation could be extended to CD4(+) and B cells in chronically infected low responder DBA/2 mice. The vascular ligand for VLA-4, VCA M-1, was found to be up-regulated on endothelial cells in sites of inf lammation, Finally, preincubation of virus-primed donor cells with mAb to VLA-4 completely blocked the ability to transfer virus-specific, d elayed-type hypersensitivity when the donor cells were given i.v., but not when the cells were injected directly into the test site. Co-tran sfer of CD8-depleted cells with anti-VLA-4-blocked cells did not revea l any cooperation. Taken together, these results indicate that VLA-LC play a critical role in lymphocyte homing during systemic virus infect ions and are involved in directing virus-specific CD8(+) effector cell s to sites of infection.