Functional Analysis of H-2-Linked Genetic Control of Immune Responsiveness to TNP-MSA

Abstract

The antibody response to trinitrophenyl-conjugated mouse serum albumin (TNP-MSA) in inbred strains of mice is regulated by a gene(s) in the I-B subregion of the H-2 complex. High responsiveness in low H-2^k × high H-2^b F1 hybrids is inherited as a recessive trait. Various parameters of the immune response to TNP-MSA were investigated to determine whether specific Ir gene activation by TNP-MSA leads to a similar or different type of regulation compared to dominant H-2-linked Ir genes. Analysis of high and low responder sera by radioimmunoassay and isoelectric focusing revealed that Ir-6 controls the production of IgG antibodies in high responder mice. Although both high and low responder immune sera contained equivalent amounts of IgM TNP-antibody, IgG anti-TNP activity was found only in high responder sera. However, low responders could be induced to produce high levels of IgG TNP-antibody after immunization with TNP-MSA complexed to a xenogeneic carrier (MBSA). Adult thymectomy and rabbit antimouse T cell serum treatment of high and low responder animals demonstrated that TNP-MSA is capable of eliciting both a T-independent IgM response and a T-dependent IgG response. The thymus-dependent IgG produced by high responder animals is of restricted heterogeneity as revealed by isoelectric focusing. High responsiveness to TNP-MSA displays either dominant or recessive inheritance in F₁ progeny depending on the H-2 haplotype combination. This finding is interpreted in terms of Ir-6 gene product interaction and hierarchical or partial dominance among multiple alleles.