Genetic control of the immune response to myoglobin. III. Determinant-specific, two Ir gene phenotype is regulated by the genotype of reconstituting Kupffer cells.

The role of macrophages in the selection of antigenic determinants able to elicit an immune response under the control of two H-2-linked Ir genes was investigated. Macrophage-depleted lymph node T cells from myoglobin-immunized (low responder x high responder) F1 (BDF1) mice, bearing both Ir genes for myoglobin from the H-2d haplotype, failed to proliferate in vitro in response to myoglobin or its fragments in the absence of added macrophages. Kupffer cells (the tissue macrophage of the liver) from H-2d mice, with both genes, reconstituted the responses to myoglobin and both the N-terminal fragment (1-55) and the C-terminal fragment (132-153), whereas H-2b Kupffer cells failed to reconstitute any of these responses. Kupffer cells from recombinant mice with only the high-responder d allele in I-A (Ir-Mb-1) reconstituted the response to myoglobin and fragment (132-153), but frequently reconstituted only a partial response to fragment (1-55). Conversely, Kupffer cells from recombinant mice bearing only the high-responder d allele in I-C (Ir-Mb-2) reconstituted the response to myoglobin and fragment (1-55), but not the response to fragment (132-153). These patterns parallel exactly the proliferative responses of intact lymph node populations of the strains from which the Kupffer cells were derived. Thus, the complete phenotype of response to determinants on an antigen under double Ir gene control is determined by the genotype of the reconstituting macrophage. This macrophage-mediated control was shown to be antigen-specific, and was not mediated through suppression induced by low-responder macrophages. Last, these observations demonstrate the exquisite immunologic functional capabilities of the Kupffer cells in determinant-specific reactions.