IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF IS REQUIRED TO SIGNAL PATHWAYS OF RECEPTOR-MEDIATED GROWTH ARREST AND APOPTOSIS IN MURINE B-LYMPHOMA-CELLS

The B cell Ag receptor is a multimeric protein complex consisting of t he ligand binding mig and the Ig alpha/Ig beta heterodimer. The cytopl asmic tails of Ig alpha and Ig beta both contain a consensus sequence termed the immunoreceptor tyrosine-based activation motif (ITAM). This motif is believed to play a critical role in the receptor-mediated si gnal transduction. To explore the role of ITAM in signaling for B cell death (apoptosis), we transfected CH31 cells, an immature B lymphoma cell line, with expression vectors encoding for the CD8 extracellular/ transmembrane domains and the cytoplasmic signal-transducing domain (I TAM) of Ig alpha or Ig beta, respectively. Here, we demonstrate that c ross-linking of CD8:Ig alpha or CD8:Ig beta with anti-CD8 mAb effectiv ely induced cell growth arrest and apoptosis characterized by [H-3]thy midine release and DNA fragmentation; in contrast, CD8:gamma 2a or tru ncated CD8:Ig alpha lacking the ITAM could not do so. Moreover, select ive point mutation of either of the two conserved tyrosine residues wi thin the ITAM, but not the nonconserved tyrosine, completely abrogated the ability of this motif to mediate cell death signals. These findin gs clearly indicate that ITAM is a critical component required for tra nsmitting growth arrest and apoptotic signals, and that these function s of ITAM are positively regulated by tyrosine phosphorylation.