We compare antibody responses to nigerose [alpha(1,3) diglucoside] when it is presented as a hapten linked to keyhole limpet hemocyanin (N-KLH) or as a native constituent of dextran (B1355). In classic terms, N-KLH is thymus dependent (TD), whereas B1355 is thymus independent (TI). N-KLH only induced an in vitro antibody response in T-depleted splenic B cells when syngeneic, KLH-specific T helper cells (TH) were supplied. This need for H-2-restricted TH could not be supplanted by the addition of lymphokines (LK). In contrast, the response to B1355 only required the addition of LK. In vivo, N-KLH induced both kappa class and lambda class antibodies, unlike B1355, which induced a response that was restricted to the lambda class. N-KLH induced a substantial IgG response in vivo, with IgG1, IgG2a, and IgG2b subclasses increasing by two to three orders of magnitude over preimmunization levels. These isotypes were not found in the in vivo response to B1355. This is consistent with the TD and TI classifications of these immunogens. Antibodies induced by N-KLH were totally inhibited by the free alpha(1,3)-linked diglucosyl hapten, nigerose, as were those induced by B1355. In vitro, B1355 also induced a lambda predominant response in naive splenic B cells. However, prepriming with N-KLH resulted in a dramatic kappa class response to B1355. The data suggest that B cells can become responsive to TI antigens after TD activation.