Genetic control of the immune response to myoglobin. VI. Inter-site influences in T-lymphocyte proliferative response from analysis of cross-reactions of ten myoglobins in terms of substitutions in the antigenic sites and in environmental residues of the sites

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The recent determination of the antigenic structure of sperm-whale Mb § and the findings that the same five antigenic sites are recognized by antibodies raised against this protein in several host species, including mouse, enabled us to focus attention on the molecular factors underlying immune recognition and responses. We have also shown that the sites recognized by mouse B-cells (antibodies) are also recognized by T-cells and that the responses to the sites are each under separate genetic control. Furthermore, we recently demonstrated that the binding capacity of an antigenic site in Mb variants is Influenced by substitutions in the antigenic sites and in residues close (within 7.0 Å) to the sites. The genetic exclusion of a response to some antigenic sites in given inbred mouse strains and the knowledge of the sites that suffer decreases or total losses in binding activity In several Mb variants affords a unique system of reduced complexity to study the molecular requirements for T-cell recognition of the Mb antigenic sites. In the present work the cross-reactions of ten myoglobins by proliferation of sperm-whale Mb-primed mouse T-cells were analyzed in terms of substitutions in the sites and in environmental residues of the sites. Help between sites 1 and 2 and between one or both of these and site 3 was observed in several mouse strains. A suppresslve Influence by site 5 on the overall proliferative response to Mb was observed in two strains (D2.GD and A.TTR4). It was concluded that the overall response to Mb is regulated by Inter-site Influences which can either be of a cooperative (help) nature or of a suppresslve nature.