Vascular cell adhesion molecule-1 (VCAM-1) expression is increased on activated endothelium, where its ability to facilitate leukocyte adherence and subsequent transmigration into tissues is associated with several diseases. VCAM-1 is also expressed by antigen-presenting cells (e.g. macrophages, dendritic cells) where it might play a role in T cell response. Indeed, several in vitro studies by others show VCAM-1 to have an impact on the magnitude of T cell activation, and on activation-induced death of chronically-stimulated T cells. Also, others have shown anti VCAM-1 antibody to reduce disease without gross reduction of leukocyte infiltration of the target tissue. Thus, we hypothesize that VCAM-1 mediates critical interactions between dendritic cells and T cells during T cell differentiation and in processes of T cell regulation. We will test our hypothesis using 'VCAM-1 -deficient' mice. Others have attempted to further investigate the in vivo roles of VCAM-1 by generating conventional VCAM-I deficient mice. Unfortunately, these efforts met with limited success due to embryonic lethality resulting from VCAM-1-deficiency, revealing an essential requirement for VCAM-l in fetal placentation. This has been overcome here by generating VCAM-1 'knock-in' mice using the Cre recombinase/loxP system. These mice express normal levels of VCAM-1 but allow deletion of the VCAM-1 gene when intercrossed with a 'TIE2Cre' Cre recombinase transgene. These conditional 'VCAM-l-deficient' mice show virtually complete loss of VCAM-1 on hematopoietic cells (including dendritic cells) and endothelial cells. These mice will be employed in studies of T cell response to antigen and T cell peripheral self-tolerance. Thus, the specific aims here are to determine the role of VCAM-1 on dendritic cells with respect to CD4+ T helper cell development, T cell activation-induced cell death and T cell peripheral self-tolerance.
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