SOLUBLE BETA(2)-MICROGLOBULIN-FREE CLASS-I HEAVY-CHAINS ARE RELEASED FROM THE SURFACE OF ACTIVATED AND LEUKEMIA-CELLS BY A METALLOPROTEASE

Regulation of the expression of major histocompatibility complex (MHC) class I heavy chains not associated with beta(2)-microglobulin (beta( 2)m) on freshly isolated and in vitro cultured human B and T leukemia cells was analyzed. These beta(2)m-free class I heavy chains originate from surface beta(2)m-associated MHC class I molecules and are expres sed as integral membrane glycoproteins on activated, but not resting, cells. We found that the levels of beta(2)m-free class I heavy chains can be regulated by proteolytic cleavage and release into the medium o f soluble molecules containing the extracellular domains. The release is mediated by a Zn2+ dependent, membrane-bound metalloprotease that d oes not cleave HLA-DR, CD4, and CD71 surface receptors and can be acti vated by phorbol myristate acetate. Specific cleavage by the metallopr otease occurs at a site close to the papain cleavage site in the alpha 3 domain of class I heavy chains. This site is not accessible to the metalloprotease in beta(2)m-associated MHC class I molecules. The diss ociation of beta(2)m-associated MHC class I molecules and subsequent c leavage of beta(2)m-free class I heavy chains may be partially respons ible for controlling the levels of MHC class I molecules on the surfac e of activated cells.