Structural aspects of immune recognition of lysozymes. III. T cell specificity restriction and its consequences for antibody specificity.

We have studied the relationship between the determinants encountered by T cells on an antigenic molecule and the specificities of the antibodies eventually produced by the B cells with which these T cells cooperate. The number of epitopes on the hen lysozyme (HEL) molecule available to T cell receptors was functionally limited by inducing T cell tolerance to HEL in rabbits. Highly cross-reactive lysozymes were then used to challenge the HEL-unresponsive rabbits. Only T cells which recognize new epitopes on the challenge lysozymes could act as helpers in generating an anti-lysozyme response. Amino acid differences between Japanese quail lysozyme (JEL) and HEL are segregated within a single quadrant of this small antigen molecule. HEL-tolerant rabbits challenged with JEL produced antibodies which were totally cross-reactive with the tolerogen HEL. This result is in contrast to the result obtained in nontolerant rabbits which produced antibodies to JEL which were only 50-70% cross-reactive with HEL. We conclude that T cells restricted to the JEL-unique epitopes were only capable of cooperating with B cells specific for common epitopes shared between JEL and the tolerogen HEL. Turkey lysozyme (TEL), on the other hand, bears different amino acids which are distributed over several regions on the surface of the molecule. Any one HEL-tolerant rabbit developed a restricted response to TEL; in some rabbits the anti-TEL was highly HEL cross-reactive, while in others little cross-reactivity with HEL was observed. Each of four HEL-tolerant rabbits injected with the minimally altered bob-white quail lysozyme possessed the reactive T cells necessary to mount a limited response to this challenge lysozyme, suggesting a diverse library of T cell specificities. Recognition of the small differences between the challenge lysozymes and the T cells of these tolerant rabbits to make a fine discrimination between minimally changed epitopes.