Assessment of the role of determinant selection in genetic control of the immune response to insulin in H-2(b) mice

The immune response to insulin is regulated by MHC class II genes, Immune r esponse (Ir) gene-linked low responsiveness to protein Ags can be mediated by the low affinity of potential antigenic determinants for MHC molecules ( determinant selection) or by the influence of MHC on the functional T cell repertoire. Strong evidence exists that determinant selection plays a key r ole in epitope immunodominance and Ir gene-linked unresponsiveness. However , the actual measurement of relative MHC-binding affinities of all potentia l peptides derived from well-characterized model Ags under Ir gene regulati on has been very limited. We chose to take advantage of the simplicity of t he structure of insulin to study the mechanism of Ir gene control in H-2(b) mice, which respond to beef insulin (BINS) but not pork insulin (PINS). Pe ptides from these proteins, including the immunodominant A(1-14) determinan t, were observed to have similar affinities for purified IA(b) in binding e xperiments, Functional and biochemical experiments suggested that PINS and BINS are processed with similar efficiency. The T cell response to syntheti c pork A(1-14) was considerably weaker than the response to the BINS peptid e. We conclude that the poor immunogenicity of PINS in H-2b mice is a conse quence of the T cell repertoire rather than differences in processing and p resentation.