Determinant hierarchy: shaping of the self-directed T cell repertoire, and induction of autoimmunity

The T cell determinants within a native antigen comprise the 'dominant' determinants, which are efficiently processed and presented, and the 'cryptic' determinants, which are poorly processed and presented, if at all. However, cryptic determinants can induce potent T cell responses in the peptide form. The 'subdominant' determinants lie in between these two extremes. The above hierarchy of determinants is of relevance both in defining the immunogenicity of a native antigen, and in tolerance induction to self antigens. Using the lysozyme model system, we have studied both the structural context of determinant hierarchy as well as its influence in shaping of the T cell repertoire, and in the induction of autoimmunity. In addition, we have examined the T cell response to lysozyme of individual members of hybrid F1 mouse strains. Our results demonstrate that: (a) each region within hen eggwhite lysozyme (HEL) is potentially available upon antigen processing; (b) the immunogenicity of a foreign/self antigenic determinant can be modulated by residues flanking the core determinant; (c) the hierarchy of determinants within mouse lysozyme (ML) has a significant influence on shaping of the T cell repertoire directed against this self protein; (d) the dominance/crypticity relationship of a given determinant within HEL/ML, respectively, might be of significance in the induction of autoimmunity; and (e) hybrid F1 mice show a broad heterogeneity of response to HEL in comparison to the parental strains. The results of these studies would be of significance in better understanding of the pathogenesis of human autoimmune diseases.