Regulatory T cells, derived from na?ve CD4+CD25- T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance.
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2005 May 27;79(10):1310-6.Regulatory T cells, derived from na?ve CD4+CD25- T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance.1, , , , , , , , , , .1Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London. jianguo.chai@csc.mrc.ac.ukAbstractBACKGROUND: Regulatory T (Treg) cells, generated in vitro by Foxp3 gene transfer into naive CD4+25- T cells, have been shown to inhibit the development of inflammation and autoimmune disease, but it is not known whether they are able to prevent allograft rejection. This study investigated whether Treg cells generated from naive CD4+ T cells by Foxp3 gene transfer could induce transplantation tolerance.METHODS: HY-specific, T-cell receptor (TCR)-transgenic CD4+25- T cells were retrovirally transduced with the Foxp3 gene. The phenotype, function, and cytokine profiles of the transduced cells were examined in vitro by fluorescence-activated cell sorter, T-cell proliferation assays, enzyme-linked immunosorbent assay, and intracellular cytokine staining. Adoptive transfer and skin grafting experiments were conducted to assess whether Foxp3-transduced HY-specific T cells could prevent the rejection of syngeneic male grafts.RESULTS: CD4+25- T cells retrovirally transduced with Foxp3 express a panel of cell surface and intracellular molecules closely associated with Treg activity. This Treg phenotype was stable during in vitro culture with some further maturation. In vitro, Foxp3-transduced cells were functionally anergic and suppressive T cells. In vivo adoptive transfer of Foxp3-transduced HY-specific TCR-transgenic CD4+ T cells protected male skin grafts from rejection by syngeneic females. Retroviral transduction of the Foxp3 gene into non-TCR-transgenic CD4+25- T cells, however, had no influence on male skin graft rejection.CONCLUSION: This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.Comment inPMID:
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):93-100.Infection-induced apoptosis deletes bystander CD4+ T cells: a mechanism for suppression of autoimmunity during BCG infection.1, , .1Trudeau Institute Inc., 154 Algonquin Ave, Saranac Lake, NY 12983, USA.AbstractInfection with Mycobacterium bovis Bacille Calmette Guérin (BCG) induces high levels of apoptosis among activated CD4+ T cells. We have investigated the specificity of this pro-apoptotic response and its influence on CD4+ T cell mediated autoimmunity. Apoptosis induced by BCG-infection is unrelated to antigenic specificity, as demonstrated by the increased apoptosis of activated TCR transgenic CD4+ T cells of unrelated specificity. Moreover, infection-induced apoptosis promoted the deletion of CD4+ T cells activated either by peptide or anti-CD3/anti-CD28 stimulation. Infection-induced apoptosis required IFN-gamma production by the infected host, and expression of the IFN-gamma receptor on donor CD4+ T cells. We used an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) to assess the influence of infection-induced apoptosis on a CD4+ T cell-mediated response. A significantly higher level of apoptosis was seen among sorted encephalitogenic CD4+ T cells transferred to BCG-infected versus uninfected hosts. BCG-infected mice displayed a milder course of clinical disease than their uninfected counterparts and a decreased recovery of donor cells from the CNS. The data suggest that mycobacterial infection attenuates the severity of EAE, at least in part, by promoting the apoptotic elimination of autoreactive CD4+ T cells.PMID:
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