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Clustering of T Cell Ligands on Artificial APC Membranes Influences T Cell Activation and Protein Kinase C Translocation to the T Cell Plasma Membrane¹

Francesca Giannoni^2,*,, Joellen Barnett^2,*, Kun Bi, Rodrigo Samodal^*, Paola Lanza, Patrizia Marchese, Rosario Billetta, Randi Vita, Mark R. Klein^*,¶, Berent Prakken^*,¶, William W. Kwok^||, Eli Sercarz^#, Amnon Altman and Salvatore Albani^3,*,

^* Departments of Medicine and Pediatrics, University of California, San Diego, CA 92093 and IACOPO Institute for Translational Medicine, San Diego/Utrecht; La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92121; Androclus Therapeutics, Milan, Italy; ^¶ Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University of Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands; ^|| Benaroya Research Institute, Virginia Mason, Seattle, WA 98101; and ^# Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

T cell activation is associated with active clustering of relevant molecules in membrane microdomains defined as the supramolecular activation cluster. The contact area between these regions on the surface of T cells and APC is defined as the immunological synapse. It has been recently shown that preclustering of MHC-peptide complexes in membrane microdomains on the APC surface affects the efficiency of immune synapse formation and the related T cell activation. Disruption of such clusters may reduce the efficiency of stimulation. We describe here an entirely artificial system for Ag-specific, ex vivo stimulation of human polyclonal T cells (artificial APC (aAPC)). aAPC are based on artificial membrane bilayers containing discrete membrane microdomains encompassing T cell ligands (i.e., appropriate MHC-peptide complexes in association with costimulatory molecules). We show here that preclustering of T cell ligands triggered a degree of T cell activation significantly higher than the one achieved when we used either soluble tetramers or aAPC in which MHC-peptide complexes were uniformly distributed within artificial bilayer membranes. This increased efficiency in stimulation was mirrored by increased translocation from the cytoplasm to the membrane of protein kinase , a T cell signaling molecule that colocalizes with the TCR within the supramolecular activation cluster, thus indicating efficient engagement of T cell activation pathways. Engineered aAPC may have immediate application for basic and clinical immunology studies pertaining to modulation of T cells ex vivo.

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