Insulitis is a hallmark feature of autoimmune diabetes that ultimately results in islet beta cell destruction. We examined integrin requirements and specific inhibition of integrin structure in T cell and monocyte adhesion to pancreatic islet endothelium. Examination of cell surface integrin expression on WEHI 7.1 T cells revealed prominent expression of ₂, ₁, _L, and low expression of _M integrins; while WEHI 274.1 monocytes showed significant staining for ₂, ₁, _M and no expression of _L molecules. Unstimulated islet endothelium showed constitutive levels of ICAM-1 counter ligand expression with minimal VCAM-1 expression; however, TNF- stimulation increased cell surface density of both molecules. TNF- increased T cell and monocyte rolling and adhesion under hydrodynamic flow conditions. Administration of a cyclic peptide competitor for the _L I domain binding sites (cLAB.L, cyclo1,12-PenITDGEATDSGC) blocked T cell adhesion without inhibiting monocyte adhesion. Examination of T cell rolling revealed that cLAB.L treatment increased the average rolling velocity on activated endothelium and significantly decreased the fraction of T cells rolling at 50 µm/sec suggesting that cLAB.L treatment interferes with signal activation events required for the conversion of T cell rolling to firm adhesion. These data demonstrate for the first time that cyclic peptide antagonists against _L I domain attenuate T cell recruitment to islet endothelium.