Soluble beta 2-microglobulin-free class I heavy chains are released from the surface of activated and leukemia cells by a metalloprotease.

Abstract

Regulation of the expression of major histocompatibility complex (MHC) class I heavy chains not associated with beta 2-microglobulin (beta 2m) on freshly isolated and in vitro cultured human B and T leukemia cells was analyzed. These beta 2m-free class I heavy chains originate from surface beta 2m-associated MHC class I molecules and are expressed as integral membrane glycoproteins on activated, but not resting, cells. We found that the levels of beta 2m-free class I heavy chains can be regulated by proteolytic cleavage and release into the medium of soluble molecules containing the extracellular domains. The release is mediated by a Zn(2+)-dependent, membrane-bound metalloprotease that does not cleave HLA-DR, CD4, and CD71 surface receptors and can be activated by phorbol myristate acetate. Specific cleavage by the metalloprotease 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 2m-associated MHC class I molecules. The dissociation of beta 2m-associated MHC class I molecules and subsequent cleavage of beta 2m-free class I heavy chains may be partially responsible for controlling the levels of MHC class I molecules on the surface of activated cells.