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DNA SEQUENCE ANALYSIS OF I-Aß MUTANTS REVEALS SEROLOGICALLY IMMUNODOMINANT REGION

The class II MHC-encoded molecules, expressed primarily by B lymphocytes, macrophages, and certain other cell types, serve as target molecules for recognition by T helper/inducer lymphocytes. The T helper/inducer cells play a critical role in regulating both cellular and humoral immunity, and thus, the antigen-specific activation of these cells triggered by the engagement of the receptor on the T cell with its ligand, an ill-defined complex of processed antigen and class II MHC molecule, is one of the key events in the activation of an immune response. It is clear that the extensive natural polymorphism of class II molecules has some relevance to their function . In the mouse, the failure of some strains to respond to certain antigens is a property of the class II alleles, and in man, susceptibility to certain disease states correlates significantly with HLA class II type. To explore the relationship between the sequence diversity and function of murine class II I-A molecules, we have produced a series of in vitro serologically selected cell lines expressing mutant I-A k molecules (1). In this report we will describe the DNA sequence analysis of four of our collection of mutant cell lines. Each of the major serologic epitopes on the A k k polypeptide has been altered in one or more of the four mutants described in this report. In addition, these four mutants exhibit a broad spectrum of functional defects when used to stimulate a panel of T hybridomas of various specificities . The DNA sequence analysis of the I-A k k gene from each mutant has revealed that each has sustained a single amino acid substitution and that all four independent substitutions have occurred within or near only one of the four variable regions defined in the 0, domain of the Aß polypeptide by allelic comparisons. These data strongly suggest that this one variable Aa mutant cell lines, five T hybridomas specific for the HEL peptide 46-61 exhibited four different patterns of stimulation by the mutant cell lines (24). These data suggest that multiple determinants can be formed by the association ofeven a sixteen-residue peptide and the I-Ak molecule, indirectly indicating the existence of several T cell recognition sites on the I-Ak molecule . Several earlier studies (25-28) had shown that the bm12 mutation (at residues 67, 70, and 71 of the A, polypeptide) had a substantial impact on antigen-presenting capability and in vivo immune responses. Direct comparisons of the ability of B6 and bm12 cells to present antigen to either B6- or bm12-derived T cell clones indirectly indicated the existence of at least two T cell recognition sites on the I-A' molecule 30). Functional studies of a limited number of site-directed Ab mutants have revealed that even those substitutions that failed to alter serologic reactivity of the molecule did affect the ability of some T cells to recognize the molecule. Lechler examined the separate contributions of the NH2- and COOH-terminal halves ofthe A,3, domain to the formation of epitopes required for recognition of antigen by a panel of I-A-restricted T hybridomas. They found that both halves of the As, domain influenced the antigen-presentation capability of the I-A molecule. Thus, it appears either that recognition by Tcells is more sensitive to structural alterations than recognition by antibodies or that at least some T cell epitopes comprised portions of the I-A molecule not directly involved in recognition by antibodies.