Tolerization during pregnancy: impact on the development of antigen-specific help and suppression

Analysis of splenic B cells in the offspring of BALB/c mice which were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) throughout the gestational period revealed that reduced responsiveness was predominantly reflecting changes in regulatory cells. Since development of T cells takes place in the thymus, postnatal maturation of helper (Th) and suppressor (Ts) T cells was evaluated in the thymus as well as in the spleen. To elaborate the impact of prenatal TNBS-treatment on the trinitrophenyl (TNP) repertoire, TNP-sheep red blood cell- and fluorescein isothiocyanate-specific regulatory elements were determined in parallel. It was found that the thymus contained activated helper and suppressor cells during the first 2 weeks of postnatal life, the majority of which appeared to be self-specific. Self reactivity in thymus and periphery disappeared within 3 weeks. Prenatally TNBS-treated mice differed inasmuch as they apparently recognized TNP-self as a self component, TNP-self reactivity being down-regulated similar to self reactivity in prenatally untreated mice. This explains why prenatally TNBS-treated mice responded poorly to stimulation with conventional T-dependent TNP-carrier conjugates. Yet, they responded transiently to TNP-anti-TNP conjugates. It could be shown that this was due to down-regulation of putatively idiotype-specific Ts, which were highly increased in prenatally TNBS-treated mice. Data are interpreted in the sense that the establishment of self tolerance is preceded by activation of self-reactive Th, which become partially eliminated. Remaining autoreactivity is controlled by the establishment on an equilibrium between idiotypic and anti-idiotypic elements.