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Ligation of CD28 by Its Natural Ligand CD86 in the Absence of TCR Stimulation Induces Lipid Raft Polarization in Human CD4 T Cells¹

Birgit Kovacs^*, Richard V. Parry, Zhengyu Ma^*, Emily Fan^*, Debra K. Shivers^*, Benjamin A. Freiberg, Anna K. Thomas, Robert Rutherford, Catherine A. Rumbley, James L. Riley^2,3, and Terri H. Finkel^2,3,*

^* Division of Rheumatology, Children’s Hospital of Philadelphia, and Departments of Medicine and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Intelligent Imaging Innovations, Denver, CO 80216

Stimulation of resting CD4 T cells with anti-CD3/CD28-coated beads leads to rapid polarization of lipid rafts (LRs). It has been postulated that a major role of costimulation is to facilitate LR aggregation. CD86 is up-regulated or expressed aberrantly on immune cells in a wide array of autoimmune and infectious diseases. Using an Ig fusion with the extracellular domain of CD86 (CD86Ig) bound to a magnetic bead or K562 cells expressing CD86, we demonstrated that ligation of CD28 by its natural ligand, but not by Ab, induced polarization of LRs at the cell-bead interface of fresh human CD4 T cells in the absence of TCR ligation. This correlated with activation of Vav-1, increase of the intracellular calcium concentration, and nuclear translocation of NF-B p65, but did not result in T cell proliferation or cytokine production. These studies show, for the first time, that LR polarization can occur in the absence of TCR triggering, driven solely by the CD28/CD86 interaction. This result has implications for mechanisms of T cell activation. Abnormalities in this process may alter T and B cell tolerance and susceptibility to infection.

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