DISTINCT STRUCTURAL COMPARTMENTALIZATION OF THE SIGNAL-TRANSDUCING FUNCTIONS OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II (IA) MOLECULES

Class II major histocompatibility complex encoded proteins (MHC class II or Ia molecules) are principal plasma membrane proteins involved in activation of both B and T cells during antigen-driven immune respons es. Recent data indicate that class II molecules are more than simply recognition elements that provide a ligand for the T cell antigen rece ptor. Changes in B cell physiology that follow class II binding are no w recognized as being required not only for the induction of T cell ac tivation, but also for B cell activation and proliferation. It is inte resting to note that class II molecules appear to transduce signals vi a two distinct mechanisms depending upon the differentiative state of the B cell on which they are expressed. While one of these pathways, i nvolving cAMP generation and protein kinase C localization in the cyto skeletal/nuclear compartment, is seen in resting B cells, the second i s seen in primed B cells and involves tyrosine kinase activation, inos itol lipid hydrolysis, and Ca2+ mobilization. Use of this pathway is c orrelated with ability of class II to transduce signals leading to B c ell proliferation. To begin to address the molecular basis of this uni que, activation-dependent, differential coupling of class II to signal ing pathways, we conducted mutational analysis of class II structural requirements for signal transduction. Here we report that the cytoplas mic (Cy) domains of I-A(k) class II molecules are not required for eit her receptor-mediated activation of protein tyrosine phosphorylation o r Ca2+ mobilization. This is in contrast to the requirement of the Cy domain of beta chain of class II for the alternate signaling pathway a nd efficient antigen presentation to autoreactive T cell lines. Dispar ate distribution of functional motifs within the MHC class II molecule s may reflect use of distinct receptor associated effector molecules t o sustain different modes of signal transduction in various class II-e xpressing cells.