2003; baxter - Supplements - Haematologica

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. Therefore, under normal circumstances,the maternal immune system is not poised toreject the allogeneic fetus, but activates mechanismsthat lead to acceptance of the fetus as self.Using pregnancy as a model to study peripheralT-cell tolerance, we have now attempted to dissectthe role of other co-stimulatory molecules intolerance induction. We find that peripheral toleranceinduction in CD8 T cells in vivo requiresCD28 co-stimulation. A model such as ours canprove useful in the elucidation of peripheral tolerancemechanisms that can ultimately bemanipulated for therapeutic purposes.References1. Kruisbeek AM, Amsen D. Mechanisms underlying T-cell tolerance. Curr Op Immunol 1996;8:233-44.2. Mondino A, Khoruts A, Jenkins MK. The anatomy of T-cell activation and tolerance. Proc Natl Acad Sci USA1996;93:2245-52.3. Kroemer, G. Clonal deletion of self-reactive T cells. InMechanisms of immunological self-tolerance. G. Kroemer,editor. R.G. Landis Co., Austin, Texas, USA. 1994.p. 16-50.4. Kisielow P, Teh HS, Bluthmann H, von Boehmer H. Positiveselection of antigen-specific T cells in thymus byrestricting MHC molecules. Nature 1988;335:730-3.5. Kappler JW, Roehm H, Marrack P. T cell tolerance byclonal elimination in the thymus. Cell 1987;49:273-80.6. Roberts JL, Sharrow SO, Singer A. Clonal deletion andclonal anergy in the thymus induced by cellular elementswith different radiation sensitivities. J Exp Med1990;171:935-40.7. Takahama Y, Shore EW, Singer A. Negative selection ofprecursor thymocytes before their differentiation intoCD4 + CD8 + cells. Science 1992;258:653-6.8. Nieuwenhuis P, Stet RJ, Wagenaar JP, Wubbena AS,Kampinga J, Karrenbeld A. The transcapsular route: anew way for (self-) antigens to by-pass the blood thymusbarrier? Immunol Today 1988;9:372-5.9. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 systemof T cell costimulation. Ann Rev Immunol 1996;14:233-8.10. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansionversus functional clonal inactivation: a costimulatorysignalling pathway determines the outcome of Tcell antigen receptor occupancy. Ann Rev Immunol1989;7:445-80.11. Schwartz RH. A cell culture model of T lymphocyte clonalanergy. Science 1990;248:1349-56.12. Boise LH, Minn AJ, Noel PJ, June CH, Accavitti M, LindstenT, et al. CD28 costimulation can promote T cellsurvival by enhancing the expression of Bcl-XL. Immunity1995;3:87-98.13. Linsley PS, Ledbetter JA. The role of CD28 receptor duringT cell responses to antigen. Ann Rev Immunol 1993;11:191-212.14. Thompson CB, Lindsten T, Ledbetter JA, Kunkel SL,Young HA, Emerson SG, et al. CD28 activation pathwayregulates the production of multiple T cell-derived lymphokines/cytokines.Proc Natl Acad Sci USA 1989;86:1333-7.15. Medawar PB. Some immunological and endocrinologicalproblems raised by the evolution of viviparity in vertebrates.Symp Soc Exp Biol 1954;7:320-38.16. Redline RW, Lu CY. Localization of fetal major histocompatibilitycomplex antigens and maternal leukocytesin murine placenta. Implications for maternal-fetalimmunological relationship. Lab Invest 1989;61:27-36.17. Chaouat G, Menu E. Maternal T cell reactivity in pregnancy?Curr Top Microbiol Immunol 1997;222:103-26.18. Beer AE, Kwak JYH, Ruiz JE. The biological basis of passageof fetal cellular material into the maternal circulation.In Ann NY Acad Sci 1993;8:21-35.19. Bonney EA, Matzinger P. The maternal immune system'sinteraction with circulating fetal cells. J Immunol1997;158:40-7.20. Carbone FR, Kurts C, Bennett SRM, Miller JFAP, HeathWR. Cross-presentation: a general mechanism for CTLimmunity and tolerance. Immunol Today 1998;368:368-73.21. Matzinger P. Tolerance, danger and the extended family.Ann Rev Immunol 1994;12:991-1045.22. Janeway CA, Goodnow CC, Medzhitov R. Immunologicaltolerance: danger - pathogen on the premises! CurrBiol 1996;5:519-22.23. Carter J, Newport A, Keeler KD, Dresser DW. FACSanalysis of changes in T and B lymphocyte populationsin the blood, spleen and lymph nodes of pregnant mice.haematologica vol. 88(supplement n. 12):september 2003