Allo-reactive memory T cells are a major barrier for induction of immunological tolerance to allografts in humans. Here, we report that stimulation of unfractionated human T cells with TLR-stimulated allogeneic plasmacytoid dendritic cells (pDCs) induces CD8+regulatory T cells (Tregs) that inhibit T-cell allo-responses, including those of memory T cells. CD3+T cells were primed for 7 days with allogeneic pDCs that had been pre-stimulated with TLR-7 or TLR-9 ligands. While the T cells proliferated and produced cytokines during the priming culture, they were profoundly hypo-responsive to re-stimulation with the same allo-antigen in a second culture. Moreover, T cells primed by pDCs exerted donor-specific suppression on allo-responses of both unfractionated and memory CD3+T cells. The regulatory capacity of pDC-primed T cells was confined to CD8+LAG-3+Foxp3+CTLA-4+T cells, which suppressed allogeneic T-cell responses through a CTLA-4-dependent mechanism. Induction of CD8+Tregs by pDCs could be partially prevented by 1-methyl tryptophan, an inhibitor of indoleamine 2,3-dioxygenase. In conclusion, stimulation of human T cells by TLR-stimulated allogeneic pDCs induces CD8+Tregs that inhibit allogeneic T-cell responses, including memory T cells. Donor-derived pDCs may be considered as an immunotherapeutic tool to prevent activation of the recipient allo-reactive (memory) T-cell repertoire after allogeneic transplantation.

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Keywords CTLA-4, Immunotherapy, LAG-3, Transplantation, Tregs
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Boor, P.P.C, Metselaar, H.J, Reyneveld-de Jong, S.D, Mancham, S, van der Laan, L.J.W, & Kwekkeboom, J. (2011). Human plasmacytoid dendritic cells induce CD8+LAG-3+Foxp3+CTLA-4+ regulatory T cells that suppress allo-reactive memory T cells. European Journal of Immunology, 41(6), 1663–1674. doi:10.1002/eji.201041229