Bacteria and viruses often use the normal biological properties of host adhesion molecules to infect relevant host cells. The outer membrane bacterial protein invasin mediates the attachment of Yersinia pseudotuberculosis to human cells. In vitro studies have shown that four members of the very late antigen (VLA) integrin family of adhesion molecules, VLA-3, VLA-4, VLA-5, and VLA-6, can bind to invasin. Since CD4+ T cells express and use these integrins, we have investigated the interaction of CD4+ T ceils with purified invasin. Although VLA integrinmediated adhesion of T cells to other ligands such as fibronectin does not occur at high levels unless the T cells are activated, resting T cells bind strongly to purified invasin. The binding of resting T cells to invasin requires metabolic activity and an intact cytoskdeton. Although CD4+ T cells express VLA-3, VLA-4, VLA-5, and VLA-6, monoclonal antibody (mAb) blocking studies implicate only VLA-4 as a T call invasin receptor. Like other integrin ligands, invasin can facilitate T call proliferative responses induced by a CD3-specific mAb. These results suggest that the nature of the integrin llgand is a critical additional factor that regulates T cell integrin activity, and that direct interactions of T cells with bacterial pathogens such as Yersinia may be relevant to host immune responses to bacterial infection.