Intracellular assembly of MHC class I heavy chains with beta 2-microglobulin occurs prior to the expression of the antigen-presenting complex on the cell surface. The association of beta 2-microglobulin with newly synthesized class I heavy chains is thought to be a strict prerequisite for their transport to the cell surface. However, MHC class I molecules not associated with beta 2-microglobulin (beta 2-microglobulin-free class I heavy chains) have been detected on the surface of activated lymphoid cells. These molecules have different conformations. Therefore, their interactions with other membrane proteins and biological functions may be different from those assigned to beta 2-microglobulin-associated MHC class I molecules. The two forms of MHC class I molecules on the surface of activated cells can self-associate and also form complexes with distinct proteins. Upon interaction with the appropriate ligands these molecular complexes transduce signals regulating cell activation. The ligand for beta 2-microglobulin-free class I heavy chains appears to be soluble CD8. A model is presented describing a novel mechanism of immunoregulation mediated by both soluble and membrane-bound forms of CD8 and beta 2-microglobulin-free class I heavy chains.