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J Biol Chem, Vol. 273, Issue 19, 11970-11979, May 8, 1998

Major Histocompatibility Class II-mediated Signal Transduction Is Regulated by the Protein-tyrosine Phosphatase CD45

Susanna F. Greer, Jiejian Lin^§, Charlotte H. Clarke^§, and Louis B. Justement^§

From the  Division of Developmental and Clinical Immunology, and Department of Microbiology, University of Alabama, Birmingham, Alabama 35294 and the ^§ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555

Major histocompatibility complex class II molecules and the B cell antigen receptor (BCR) transduce similar signals when cross-linked by ligand. Therefore, studies were conducted to determine whether the protein tyrosine phosphatase CD45 regulates signaling via these transmembrane receptors in an analogous manner. Cross-linking of either class II molecules or the BCR on CD45-positive K46-17µm B lymphoma cells was observed to induce activation of the Src family protein- tyrosine kinase Lyn, tyrosine phosphorylation of Syk and phospholipase C, and the production of inositol 1,4,5-trisphosphate leading to intracellular mobilization as well as extracellular influx of Ca²⁺. In the absence of CD45, cross-linking of either class II molecules or the BCR failed to induce activation of Lyn. Syk was inducibly phosphorylated on tyrosine in a normal manner, whereas phospholipase C exhibited a high basal level of tyrosine phosphorylation that was not significantly increased upon stimulation. Nevertheless, phospholipase C appeared to be functional because CD45-negative cells produced elevated levels of inositol 1,4,5-trisphosphate following stimulation through class II or the BCR. Regardless of this, CD45-negative cells exhibited Ca²⁺ mobilization responses that were greatly diminished and transient in nature. Whereas little or no mobilization of Ca²⁺ was observed in response to class II cross-linking, CD45-deficient cells mobilized Ca²⁺ from intracellular stores but not the extracellular environment in response to BCR cross-linking. These results demonstrate that CD45 regulates both Src family kinase activation and Ca²⁺ mobilization associated with class II- and BCR-mediated signal transduction.

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