A small hypervariable segment in the variable domain of an immunoglobulin light chain stimulates formation of anti-idiotypic suppressor T cells.

The induction in BALB/c mice of suppressor T cells that block a delayed-type hypersensitivity (DTH) response to the idiotype of M315, a myeloma protein of BALB/c origin, was examined with a variety of immunoglobulin chains and fragments whose amino acid sequences are known. Normal BALB/c mice receiving either the light chain of M315 (L315, lambda 2 isotype) or the variable (V) domain of this chain prior to sensitization with M315 showed marked suppression of DTH to the M315 idiotype. In contrast, neither the heavy chain nor the variable domain of the heavy chain of M315 affected the DTH response. Two other lambda 2 chains were tested and they also failed to suppress DTH to M315. Comparison of amino acid sequences in the three lambda 2 chains indicates that in L315 at most four V region amino acid substitutions (each resulting from a somatic mutation in the V lambda 2 germ-line gene) determine the specificity of the T-cell suppressor pathway. One of the four is in the framework and probably of negligible importance; the other three, however, are all clustered in the third hypervariable loop of the L315 V domain. The tertiary structure of L315 may also be essential, because disruption of intrachain disulfide bonds abolished the ability of the chain to induce suppression.