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The Cytoplasmic Tail of the T Cell Receptor CD3 Subunit Contains a Phospholipid-Binding Motif that Regulates T Cell Functions

LauraM. DeFord-Watts^*, Tara C. Tassin, Amy M. Becker^*, Jennifer J. Medeiros^*, Joseph P. Albanesi, Paul E. Love^¶, Christoph Wülfing^*, and Nicolai S.C. van Oers^*,

^*Department of Immunology, Department of Pharmacology, Department of Microbiology, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and ^¶Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

The CD3 subunit of the TCR complex contains two defined signaling domains, a proline-rich sequence and an ITAM. We identified a third signaling sequence in CD3 , termed the basic-rich stretch (BRS). Herein, we show that the positively charged residues of the BRS enable this region of CD3 to complex a subset of acidic phospholipids, including PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P₃, and PI(4,5)P₂. Transgenic mice containing mutations of the BRS exhibited varying developmental defects, ranging from reduced thymic cellularity to a complete block in T cell development. Peripheral T cells from BRS-modified mice also exhibited several defects, including decreased TCR surface expression, reduced TCR-mediated signaling responses to agonist peptide-loaded APCs, and delayed CD3 localization to the immunological synapse. Overall, these findings demonstrate a functional role for the CD3 lipid-binding domain in T cell biology.

Address correspondence and reprint requests to Nicolai S. C. van Oers, Room NA2.200, 6000 Harry Hines Boulevard, Department of Immunology, University of Texas, Southwestern Medical Center, Dallas, TX 75390-9093. E-mail address: nicolai.vanoers{at}utsouthwestern.edu