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AP2 Adaptor Complex-Dependent Internalization of CD5: Differential Regulation in T and B Cells¹

Xianghuai Lu^2,*, Robert C. Axtell^*, James F. Collawn, Andrew Gibson^*, Louis B. Justement and Chander Raman^3,*

^* Division of Clinical Immunology and Rheumatology, Departments of Medicine, Cell Biology, and Microbiology, University of Alabama, Birmingham, AL 35294

CD5 is a key regulator of Ag receptor-mediated activation, selection, and differentiation in both T and B cells. Accumulating evidence indicates that lymphocyte activation and selection are sensitive to variations in levels of CD5 on the cell surface. We now show that CD5 expression on the surface of B and T cells is regulated posttranslationally by direct interaction with the µ₂ subunit of the AP2 adaptor complex that links transmembrane proteins to clathrin-coated pits. CD5 is rapidly internalized from the cell surface in lymphoid cell lines, mature splenic T and B cells, and peritoneal CD5⁺ B cells following monovalent or bivalent ligation of the receptor. We mapped the µ₂ subunit binding site on CD5 to Y⁴²⁹ and determined that the integrity of this site was necessary for CD5 internalization. Cross-linking of the Ag receptor with intact Abs inhibited CD5 internalization in B cells, but had the opposite effect in T cells. However, if F(ab')₂ Abs were used to stimulate the Ag receptor in B cells, the effect on CD5 internalization was now similar to that observed in T cells, indicating that signals through the Ag receptor and FcR regulate CD5 endocytosis in B cells. This was confirmed using an FcRIIB1-deficient B cell line. The ability to differentially alter posttranslational CD5 expression in T and B cells is likely to be key in regulation of Ag receptor signaling and generation of tolerance in T and B lymphocytes.

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