HLA Class I Molecules Partner with Integrin β4 to Stimulate Endothelial Cell Proliferation and Migration

Among transplant recipients, those who produce antibodies against the donor's human leukocyte antigens (HLAs) are at higher risk for antibody-mediated rejection and transplant vasculopathy, which is a progressive, vasculo-occlusive disease that results in ischemic injury and deterioration of organ function. Antibodies against HLA class I (HLA-I) molecules are thought to contribute to transplant vasculopathy by triggering signals that elicit the activation and proliferation of endothelial cells. Here, we demonstrate a molecular association between HLA-I and the integrin beta(4) subunit after the stimulation of endothelial cells with HLA-I-specific antibodies. Knockdown of integrin beta(4) in these cells abrogated the ability of HLA-I to stimulate the phosphorylation of the kinases Akt, extracellular signal-regulated kinase (ERK), and Src, as well as cellular proliferation. Similarly, reducing the abundance of HLA-I suppressed integrin beta(4)-mediated phosphorylation of ERK and the migration of endothelial cells on laminin-5, a component of the extracellular matrix. These results indicate a mutual dependency between HLA-I and the integrin beta(4) subunit to stimulate the proliferation and migration of endothelial cells, which may be important in promoting transplant vasculopathy and tumor angiogenesis.