Tolerance induction during ontogeny. II. Distinct unresponsive states in immature mice question the generality of clonal abortion.

Multivalent trinitrophenyl (TNP) conjugates of both human gamma-globulin (HGG) and bovine serum albumin (BSA) are capable of inducing hapten-specific unresponsiveness in neonatal mice, as assessed by challenge with TNP on thymus-dependent carriers. When such mice are challenged with TNP on thymus-independent carriers, however, only TNP-HGG- but not TNP-BSA-treated mice are found to be substantially unresponsive to the hapten. Moreover, unresponsiveness induced by BSA, but not HGG, as a carrier was associated with the presence of antigen-specific suppressor cells. Thus, contrary to predictions made by defendants of the classical clonal abortion hypothesis, functional deletion of hapten-specific B cells appears to depend on the nature of the hapten-carrier complex. This conclusion is supported by B cell-precursor frequency estimates indicating that the number of hapten-specific precursor cells is significantly lower in TNP-HGG-treated mice, but remains unaltered in TNP-BSA-treated mice relative to the precursor frequency in untreated animals. While it remains a formal possibility that the differences in tolerogenicity seen between the two carriers can be interpreted in terms of a difference in serum half-life, we favor the interpretation that the distinction lies in molecular aspects of the carrier, which allow for differences in antigen handling by sets of interacting cells.