HINDRANCE OF BINDING TO CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX-MOLECULES BY A SINGLE AMINO-ACID RESIDUE CONTIGUOUS TO A DETERMINANT LEADS TO CRYPTICITY OF THE DETERMINANT AS WELL AS LACK OF RESPONSE TO THE PROTEIN ANTIGEN

The immune system has evolved the potential to respond to a wide varie ty of antigens, yet unresponsiveness to many foreign determinants is e ncountered frequently, Here, we report a lack of response to a particu lar determinant, hen egg lysozyme (HEL)-(46-61)-peptide (p46-61), in C 57BL/6 (H-2(b)) mice, whereas a strong T-cell response to this determi nant is obtained in major histocompatibility complex (MHC)-identical C 3H.SW mice. However, (C3H.SW x C57BL/6)F-1 mice respond well to p46-61 , suggesting the absence of a p46-61-specific ''hole'' in the T-cell r epertoire in C57BL/6 mice, We further show that p46-61 cannot bind the I-A(b) class II MHC molecule, whereas p46-60 lacking Arg(61) exhibits good binding and is immunogenic in both strains, Thus, the presence o f the hindering residue, Arg(61), renders p46-61, a dominant determina nt in C3H.SW, into a silent, cryptic determinant in C57BL/6 mice, Upon i,p, immunization with HEL, no T-cell responses to either HEL or p46- 61 could be demonstrated in spleens of HEL- primed C57BL/6 mice, where as a predominant response to p46-61 and HEL was demonstrated in C3H.SW mice, Evidently, C57BL/6 mice differ from C3H.SW in their ability to process p46-61 into an actual I-A(b) binding determinant, indicating a putative enzymatic defect in the C57BL/6 strain. Furthermore, our res ults suggest that the inability of C57BL/6 mice to respond in the sple en to HEL is based upon its failure to generate a dominant immunogenic determinant from HEL, coupled with its pattern of susceptibility to r egulatory effects.