Antigen processing for presentation to T lymphocytes: function, mechanisms, and implications for the T-cell repertoire.

Antigen processing encompasses the metabolic events that a protein antigen must undergo in or on the antigen-presenting cell before it can be recognized by the T lymphocyte. It appears that a primary goal of these events is to unfold the protein to expose residues that are buried in the native conformation, which is designed to be soluble in water. The APC usually accomplishes this task by proteolytic cleavage of the protein, but we have found that artificial unfolding without proteolysis is sufficient. The purpose of unfolding may be to allow different faces of the antigenic site to bind simultaneously to the T-cell receptor and the MHC molecule on the APC, or to interact with other structures on the membrane of the APC. This requirement for unfolding appears to apply to everything from small peptides to large multimeric proteins. We have found that the way the antigen is processed and the structure of the fragments produced can greatly affect the availability of antigenic sites. For instance, some antigenic sites are not recognized when the native protein is used as immunogen, despite the fact that immunization with a small peptide corresponding to that site reveals both the ability of the site to bind to MHC molecules of the animal in question and the presence of a T-cell repertoire specific for that site. The antigenic site is not destroyed by processing, since it can be presented by the same F1 APC to T cells of another MHC type. Similarly, cross-reactivity between homologous epitopes of related proteins may occur at the peptide level even though the native proteins do not crossreact for the same T-cell clone. Since these events occur with monoclonal T cells, they cannot be due to suppressor cells specific for other sites on the native molecule. The best explanation is that the products of natural processing of the protein are larger than the peptides corresponding to the minimal antigenic sites, and contain hindering structures that interfere with binding to some MHC molecules and not others, or to some T-cell receptors and not others. Thus, antigen processing is a third factor that can lead to apparent Ir gene defects - in addition to MHC specificity and holes in the T-cell repertoire - and can significantly influence which antigenic sites are immunodominant.(ABSTRACT TRUNCATED AT 400 WORDS)