The specificity of the interaction between the agretope of an antigen and an Ia-molecule can depend on the T cell clonotype.

A series of T cell clones was developed from (B10 x B10.BR)F1 mice immunized with the isolated A chain of pig insulin. The T cell clones show considerable diversity as defined by their distinct reactivities to pig, beef, sheep and horse insulins in combination with the same syngeneic Ab alpha Ak beta molecules. These species variants of insulin differ from each other only in amino acid residues in position A8, A9 or A10 within the so-called A chain loop and responsiveness of mice to these variants is under Ir gene control. A detailed analysis of the stimulatory capacity of various insulin/Ia combinations including inhibition experiments with anti-Ia- and -L3T4 antibodies led to the following interpretation: the amino acid residues A8-A10 are involved in the interaction of the insulin A chain with the Ia molecules. This region can, therefore, be regarded as part of the agretope. Structural variations within this region can modify the stimulatory potency of the insulin variants. However, whether a particular amino acid substitution results in an enhancement or a reduction of the response depends on the fine specificity of the T cell clone involved. Thus, an interaction of Ia molecules with antigen cannot solely account for the functional specificity of an agretope, rather this also depends on the structure of the particular T cell receptor that participates in recognition.