104M.S. Vacchio et al.reported that two kinds of anergy can be inducedin vitro, one that is induced by TCR stimulationin the absence of CD28 and is reversible by interleukin-2(IL-2) and the other that is induced byCTLA-4 signals and is not reversible by IL-2. 39The antigen-specific unresponsiveness that wehave observed in H-Y specific transgenic T cellsresembles the second of these anergic states, inthat it is not reversible by IL-2. 33 However in ourmodel of peripheral tolerance, anergy inductiondoes not occur in CD28 knockout mice, despitethe fact that CTLA-4/B7 interactions remainintact in these animals.The dependence on CD28 co-stimulation forthe induction of peripheral tolerance in this systemis in striking contrast to what has beenobserved in CD4 T cells. The observation that H-Y specific T cells did not require CD28 co-stimulationfor activation, as well as the fact thatCD28 is required for peripheral tolerance, haveimportant implications for the development oftolerance-inducing therapies. Because the majorityof work studying the role of CD28 has beenperformed with CD4 T cells, many current therapiesare being designed with the approach thatblockade of CD28 could not only prevent T-cellactivation but induce T-cell anergy. Our workwith CD8 T cells suggests that activation canoccur in the absence of CD28. Moreover, CD28signals can actually be required for toleranceinduction. While our data are representative of asingle antigen-specific T cell, these finding suggestthat activation and tolerance-inductionrequirements can differ between CD4 and CD8T cells; a point to be considered in the design oftolerance-inducing therapies.ConclusionsWhile others have focused on the fetus as anallograft, we have tested the hypothesis that thefetus is responded to as a tissue expressing developmentally-regulatedself antigens, and that T-cell responses to the fetus may be representativeof peripheral mechanisms of T-cell tolerance.Accumulating experimental evidence using antigen-specificsystems to address the fate of maternalT cells upon encounter with fetally-derivedantigens has demonstrated that these cells canundergo several fates. The identified responses ofT cells to the fetal antigens include antigen-specificnon-responsiveness and clonal elimination.These mechanisms are observed in response toself-antigens in other peripheral self-tolerancemodels. 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