A possible immunodominant epitope recognized by murine T lymphocytes immune to different myoglobins.

We find that a single region on the surface of different species of myoglobin appears to be immunodominant for T lymphocytes, even though the residues in that region vary sufficiently that the T cells immune to one myoglobin do not crossreact with other myoglobins bearing substitutions at that site. Immunization of B10.S mice with sperm whale myoglobin elicits T-lymphocyte populations capable of recognizing sperm whale myoglobin but not horse myoglobin, whereas the converse is true when these mice are immunized with horse myoglobin. Using a series of myoglobin variants, we tested the effect of changes in primary sequence on the T-lymphocyte proliferative response. We were able to divide the myoglobin variants into two groups, depending on whether they cross stimulate sperm whale immune or horse immune T lymphocytes. The patterns of cross stimulation of both populations of myoglobin immune T lymphocytes were explained by amino acid substitutions at position 109. However, because sperm whale and horse myoglobin differ at this residue (glutamate vs. aspartate, respectively), T lymphocytes immune to each myoglobin do not crossreact with the other myoglobin. Additional data suggest that this immunodominant epitope also includes other residues nearby on the surface of the native molecule. Mixing experiments showed that the specificity was that of T lymphocytes and not antigen-presenting cells. Monoclonal anti-I-A blocking studies showed that both myoglobins are presented in association with the same Ia antigen. Possible explanations for the apparent immunodominance of this antigenic epitope, consisting of residue 109 and nearby residues on the surface of both myoglobins, include a peculiar immunogenicity of the surface topography of this site of a preferred orientation of the molecule imposed by antigen-presenting cells when T cells first encounter the antigen. The latter explanation is related to but distinct from "determinant selection." T-cell recognition of conformation is discussed.