IMMUNODOMINANCE IS INDEPENDENT OF STRUCTURAL CONSTRAINTS - EACH REGION WITHIN HEN EGG-WHITE LYSOZYME IS POTENTIALLY AVAILABLE UPON PROCESSING OF NATIVE ANTIGEN

Upon challenge with native Ag and later recalling the response in vitr o using synthetic peptides, the responses to different T cell determin ants can be categorized as dominant, subdominant, or cryptic (1). It h as been reported in different experimental systems that T cell respons es to a protein Ag (e.g., hen eggwhite lysozyme (HEL),(3) cytochrome c , OVA, sperm whale myoglobin, staphylococcal nuclease, lambda represso r, influenza virus hemagglutinin, and ragweed allergen) are focused on to a few determinants, termed the ''immunodominant'' determinants (2-1 2). A variety of explanations have been proposed to explain immunodomi nance of certain determinants over others within an Ag (reviewed in Re fs. 1, 4, and 8), for example: 1) special structural properties intrin sic to certain regions of an Ag (reviewed in Ref. 8); 2) efficient pro cessing of these determinants from native Ag (relative availability) ( 13, 14); 3) better binding of certain determinants to a particular MHC molecule (15, 16); 4) promiscuous binding of a peptide to different M HC molecules (17, 18); 5) competition between determinants for binding to the same or different MHC (4, 19-21); 6) the number of MHC/peptide complexes presented on the surface of the APC as well as their stabil ity (22), which is a function of several of the above; 7) the proofrea ding action of nonclassical class II, H-2 M/DM, which favors presentat ion of long-lived MHC class II/peptide complexes to T cells (23, 24); and 8) a higher frequency of T cells potentially reactive to the immun odominant determinant in the mature T cell repertoire (4, 8, 10, 25), etc. In this study, we have addressed three important questions regard ing immunodominance using HEL as a model Ag: first, are only certain r egions within HEL revealed as immunodominant, while other areas within the molecule are either rarely, if ever, utilized or never become rev ealed upon challenge with HEL, owing to structural constraints? Second , is the response to HEL of congenic, MHC-disparate mouse strains with identical non-MHC genes restricted to one or more members of a set of determinants as a result of any processing constraints imposed by the background genes? Third, how different is the pattern of immunodomina nce of determinants within HEL in mice having a truncated TCR repertoi re compared with wild-type mice? Our results from 19 strains of mice w ith 11 different MHC haplotypes suggest that each contiguous region of HEL has the potential to be immunodominant, and thereby immunodominan ce or immunorecessiveness is not structurally favored or constrained, respectively, by the primary or secondary structure of the Ag. Further more, even under apparently similar Ag-processing conditions, the immu nodominant determinants of HEL responded to by various mouse strains a re distributed all over the molecule; however, the identity of determi nants displayed by different strains is primarily determined by the MH C of the host. Finally, our results show that mice having a truncated TCR repertoire can sometimes lose response to certain immunodominant d eterminants of HEL, but apparently their ability to raise a response t o native HEL is not seriously compromised.