HLA CLASS II-INDUCED TRANSLOCATION OF PKC-ALPHA AND PKC-BETA-II ISOFORMS IS ABROGATED FOLLOWING TRUNCATION OF DR-BETA CYTOPLASMIC DOMAINS

Several studies have attempted to identify regions of the MHC class II molecule that participate in signal transduction. The importance of i ntact murine I-A cytoplasmic domains, either to tether the class II mo lecule to the cytoskeleton or to recruit signal-transducing proteins, is now well established. Recent data have also suggested that residues of the I-A beta transmembrane are involved in a second distinct signa ling pathway. In the light of data suggesting that the second messenge rs activated can ligation of human and mouse class II molecules may di ffer, we set out to investigate whether the structural requirements fo r signaling for the human DR molecule are similar to those already des cribed for the murine I-A molecule. We show that mutant DR class II mo lecules lacking 12 amino acids of the beta-chain cytoplasmic tail fail to translocate the protein kinase C alpha (PKC alpha) and PKC beta II isoenzymes following stimulation with an anti-class II mAb. In contra st, truncation of either or both cytoplasmic domains of the DR molecul e has no effect on class II-induced tyrosine kinase activity. PKC tran slocation following class II stimulation has been observed in both hum an and murine B lymphocytes, whereas tyrosine kinase activation is pre sent in human B lymphocytes but absent in resting murine B lymphocytes . Therefore, we conclude that the DR beta cytoplasmic tail is requisit e for the principal signaling pathway initiated via MHC class II. Thes e data suggest that the signaling pathways seen in resting vs primed m urine B cells may also operate in human APCs.