Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice

Abstract

The ease of tolerance induction in B [bone marrow-derived] lymphocytes from fetal, neonatal and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG [bovine .gamma.-globulin], DNP6-D-GL [dinitrophenylated copolymer of D-glutamic acid and D-lysine] and ultracentrifuged DNP22-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with BGG or DNP44-BGG between 4 and 14 days after tolerance induction. With BGG, no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8 day old spleen, adult spleen or adult bone marrow. B cells from 14 day fetal donors are relatively resistant to tolerance induction. DNP6-D-GL and DNP22-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP6-D-GL or DNP22-BGG. Neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. There apparently are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG, which do not have repeated epitopes, no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.