title: Human plasmacytoid dendritic cells induce CD8⁺ LAG-3⁺ Foxp3⁺ CTLA-4⁺ regulatory T cells that suppress allo-reactive memory T cells.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Patrick P C
authors.initials: PP
authors.lastname: Boor
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Sarina de
authors.initials: Sd
authors.lastname: Jonge
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D016827:CD8 Antigens / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007519:Isoantigens; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C028129:tryptophan methyl ester; D014364:Tryptophan; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human