A new cross-reactive idiotope family (CRIAD8) is described that contains subpopulations of antibodies binding to different epitopes. One subpopulation occurs naturally in normal sera from strain A mice, is found mainly on IgG2 and IgG3 subclasses, does not bind p-azobenzenearsonate (ABA)+, does not express CRI5Ci, and can be selectively stimulated by low doses of antiidiotype antibody (AD8). The second subpopulation is not found in normal serum, binds ABA, is found on all IgG subclasses, expresses CRI5Ci, and is selectively stimulated by ABA-conjugated proteins. Since CRIAD8 was found on both subpopulations of antibody, and since each subpopulation could be selectively expanded, it was possible to study the effect that expansion of the ABA- CRIAD8+ set had on subsequent responses elicited by ABA-keyhole limpet hemocyanin (KLH) in the ABA+ CRIAD8+ set. In these experiments, prior immunization with AD8 restricted the subsequent response of the ABA+ CRIAD8+ set to ABA-KLH. Furthermore, only those doses of AD8 that stimulated the ABA-CRIAD8+ set reduced the responsiveness of the ABA+ CRIAD8+ set to ABA-KLH, suggesting that the two phenomena are causally related. These findings argue that CRIAD8 correlates well with a regulatory idiotope and that immune responses by lymphocyte clones that have different antigen-binding specificities can affect one another as a result of their sharing such an idiotope. These results strongly favor a network organization of the immune system.