H-2 Effects on cell-cell interactions in the response to single non-H-2 alloantigens - VI. H-2K^b mutants differentially regulate the immune response to the H-4.2 alloantigen

Mice expressing mutant H-2K^b alleles were tested for their ability to generate cytotoxic effector T-cells specific for the non-H-2 histocompatibility alloantigen H-4.2. Cytotoxic effectors specific for H-4.2 are preferentially restricted by the K^b allele. Mutant K^b alleles were observed to differentially regulate the magnitude of the H-4.2-specific cytotoxic effector response. Mice expressing the K^bm5, K^bm6, K^bm7, and K^bm9 alleles generated cytotoxic T-cells to the same level as mice expressing the wild-type K^b allele. K^bm8 and K^bm11 responders generated intermediate levels of effectors, whereas K^bm1, K^bm3, and K^bm10 responders did not generate detectable levels of cytotoxic effectors. K^bm4 responders produced high levels of H-4.2-specific cytotoxic effectors that were variably reactive with wild-type K^b antigens with no H-4.2. The ability to generate H-4.2-specific effectors generally correlated with (1) the ability of mutant K^b molecules to present H-4.2 to wild-type K^b-restricted effectors, and (2) the position of the respective amino acid interchanges on the K^b molecule. Mutations that altered the amino acid sequence in the vicinity of the disulfide bond in the C1 domain had the greatest deleterious effects on K^b-controlled responsiveness to H-4.2. The only exception was the K^bm11 intermediate responder, which differs from K^bm3 in both responsiveness and in a single amino acid interchange. Therefore, the amino acid sequence in the vicinity of the disulfide bond in the C1 domain plays a prominent role in determining the H-4.2-specific immune response potential. These observations are the first to clearly demonstrate association between particular MHC gene product, amino acid sequences and immune responsiveness.