2003; baxter - Supplements - Haematologica

102M.S. Vacchio et al.in circulation have been shown to be weakly positivefor expression of classical class I moleculessuggesting that upregulation may occur outsidethe placental environment. 17 Thus, maternal Tcells could conceivably encounter fetal antigensvia exported MHC-expressing trophoblasts presentin the maternal tissues (Figure 2a). Thiswould implicate the trophoblasts as potentialAPCs and provide a means by which peripheral Tcells could encounter fetally-derived antigens.Alternatively, cellular proteins from the fetallyderivedtissues may be presented to maternal Tcells after uptake by maternal professional APCs(dendritic cells, macrophages and B cells) andmigration to lymphoid organs, as has been proposedin the model of cross-presentation(Figure2b). 20There has been extensive discussion of Medawar’sproposal that the fetus represents nature’sallograft. 15 Viewing the fetus in the context of theimmune system's ability to distinguish self fromnonself, the fetus would fall under the category ofnon-self since many of the gene productsexpressed by the fetus may not even be encodedby the maternal genome and therefore, have neverbefore been encountered. Yet, the immune systemdoes not mount an immune responseagainst the fetus as it would a transplanted tissue.While there may be disparate MHC expressed,the dynamics of the interaction between themother and fetus are far different from that of aclassical allograft with the recipient immune system.Mature T cells in a non-inflammatory setting,for the most part, become tolerized uponencounter with antigen, whether self or foreign.Activation of T cells in response to antigen hasbeen proposed to depend on the presence of asecond danger signal, such as those generatedduring tissue destruction, 21,22 resulting in theactivation of APCs that would lead to inductionof T-cell effector function. However, during pregnancythere is not an immediate threat to themother posed by the fetus. The encroachmentand establishment of the fetus into the maternaluterus is invasive but with minimal tissue damageas compared to that of transplantation of atrue allograft, such as a transplanted kidney. Furthermore,the placental separation of maternal/fetalcirculatory systems and relatively lowlevels of allogeneic MHC class I and absence ofclass II antigens on the placenta would minimizethe amount of immediate antigenic challenge.This is in stark contrast to tissue transplants inwhich the recipient’s immune system is confrontedwith a potent antigenic challenge incombination with tissue damage and potentialadventitious pathogens. In view of the inflammatorysituation of tissue transplantation, theencounter of maternal T-cells with fetal antigenswould be more innocuous and seem to be littlemore than an encounter with a developmentally-regulatedor tissue-specific self-antigen.Encounter with the fetal tissues should thereforebe little different than encounter with any otherFigure 2. How do fetal antigens encounter maternal T cells?Maternal T cells can potentially encounter fetal antigens inseveral ways: either presentation via MHC-expressing trophoblaststhat escape into the maternal circulation (a) or“cross-presentation” of fetal antigens by maternal APCs (b).organ present in the mother. In addition, unlikea transplanted kidney, the fetus employs multiplemechanisms designed to ensure acceptanceby the maternal immune system. Given the noninflammatorynature of pregnancy, we proposethat maternal T-cell responses upon encounterwith fetal antigens during pregnancy may be representativeof how mature T cells respond uponencounter with self-antigens in the periphery.Therefore, we propose that maternal T cellswould become tolerized to fetal antigens ratherthan immunized against them during a normalpregnancy.T-cell tolerance to fetal antigensGiven our proposal that the fetal antigensmore closely resemble tissue-specific self-antigensthan alloantigens, we postulated that maternal Tcells should become tolerized to fetal antigens.Many people have attempted to characterize anylymphocytic changes that may occur in thematernal immune system in the hope of understandinghow these changes reflect maternalresponsiveness or tolerance to the fetus. Unfortunately,these studies have often yielded resultsthat are conflicting or difficult to interpret, withno firm consensus concerning the antigen-specificresponse to the fetus, primarily due to thedifficulty in interpreting changes in heterogeneousT-cell populations. 23-31 The generation ofTCR transgenic mice has allowed us to visualizethe fate of maternal T cells during pregnancy. Inthese mice, the majority, if not all of the T cellsexpress a transgenic TCR of known antigenicspecificity and MHC restriction. Therefore, thefate of T cells specific for a given antigen afterhaematologica vol. 88(supplement n. 12):september 2003