Administration of an ICAM-1–specific antibody arrests dendritic cells in a semi-immature state and facilitates antigen-specific T cell tolerance to islet allografts in humanized mice and Rhesus monkeys.

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We investigated the co-stimulatory role of a cellsurface protein, CD99. Co-ligation of CD99 and suboptimal CD3 induced T-cell activation to a level comparable to that obtained with optimal CD3 or CD3+CD28. We also noted concomitant enhancement of the earliest T-cell receptor (TCR) signaling events. In addition, co-ligation of CD99 and CD3 led to translocation of TCR complexes into the lipid raft, without concomitant migration of CD99 to the raft, and consequent enhancement of TCR ζ-mediated signal 1. These data demonstrate the unique properties of CD99 co-stimulation that distinguish this molecule from CD28 and other raft-resident costimulatory factors.Keywords: antigens; lymphocyte activation; receptors, antigen, T-cell; signal transduction; T lymphocytes IntroductionThe physiological process of T-cell activation can be divided into a series of temporal stages consisting of initial adhesion, initial signaling (formation of the contact cap), and sustained signaling (Bromley et al., 2001). During these stages, two independent signals are required for the enactment of full T-cell activation: (1) specific interaction of a T-cell receptor (TCR) with a cognate peptide/MHC on APCs, and (2) the ligation of surface co-stimulatory molecules with specific ligands on APCs. Among the known costimulatory molecules, CD28 launches the most effective activation of T cells (Alegre et al., 2001;. However, recent reports have suggested that many other candidates, most of which reside in the lipid raft, induce T-cell activation as potently as CD28 does (Denning et al., 1988;Ledbetter et al., 1988;Green et al., 1994;Tai et al., 1996;Yashiro-Ohtani et al., 2000;Stillwell and Bierer, 2001).The lipid raft is a unique membrane microdomain that is enriched with specific types of lipids and cholesterol and is associated with many key molecules involved in TCR signaling. Upon engagement of cognate ligands (peptide/MHC), TCRs are recruited toward the raft along with a series of tyrosine-phosphorylated signaling molecules (Moran and Miceli, 1998;Xavier et al., 1998;Janes et al., 1999). The lipid raft thus serves as a stage for protein-protein interactions among many surface molecules, thereby instigating a series of signaling cascades following TCR engagement (Cherukuri et al., 2001).CD99, a monomeric 32-kDa transmembrane glycoprotein, is the product of mic2 and lacks significant homology to any functional or structural domains of known proteins (Schenkel et al., 2002). Ligation of CD99 with anti-CD99 mAb induces homotypic aggregation and apoptosis of thymocytes (Bernard et al., 1997) as well as up-regulation of cell-surface proteins, such as TCR and MHC classes I and II . A recent report suggested that reorganization of the cytoskeleton is involved in the function of CD99 (Cerisano et al., 2004).In this study, we explored the possible role and mechanism of CD99 as a co-stimulatory molecule in T-cell activation. CD99 engagement leads to the CD99 activates T cells via a costimulatory function that promotes raft association of TCR comp...