title: Generation of highly suppressive adaptive CD8(+)CD25(+)FOXP3(+) regulatory T cells by continuous antigen stimulation.
abstract: Continuous antigen stimulation of CD4(+)CD25(-) T cells leads to generation of adaptive CD4(+)CD25(+)FOXP3(+) regulatory T (T(R)) cells. Here, we show that highly suppressive adaptive CD8(+)CD25(+)FOXP3(+) T cells can be generated in the same manner by continuous antigen stimulation in the presence of CD14(+) monocytes. During the course of stimulation, acquisition of immunosuppressive properties develops in parallel with up-regulation and expression of cytotoxic molecules. The CD8(+) T(R) cells inhibit CD4(+) and CD8(+) T cell proliferation and cytokine production, but do not alter the expression of granzyme A and granzyme B or perforin in CD8(+) effector T cells. Although, the CD8(+) T(R) cells express prostaglandin E(2), IL-10 and TGF-beta, the mechanism of suppression was independent of these soluble factors. In contrast to adaptive CD4(+) T(R) cells, the CD8(+) T(R) cells suppress mainly by a contact-dependent mechanism as evident from transwell experiments. However, neither blocking antibodies to CTLA-4, CD80 nor CD86 could reverse CD8(+) T(R)-mediated suppression, indicating that other mechanism(s) must be employed by these cells.
authors.affiliation: Biotechnology Centre and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Norway.
authors.forename: Milada
authors.initials: M
authors.lastname: Mahic
authors.forename: Karen
authors.initials: K
authors.lastname: Henjum
authors.forename: Sheraz
authors.initials: S
authors.lastname: Yaqub
authors.forename: Bjørn Atle
authors.initials: BA
authors.lastname: Bjørnbeth
authors.forename: Knut Martin
authors.initials: KM
authors.lastname: Torgersen
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.forename: Einar Martin
authors.initials: EM
authors.lastname: Aandahl
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology; D018106:CD28 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D054353:Perforin / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D000942:Antigens, Bacterial; D018106:CD28 Antigens; D004768:Enterotoxins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053645:Interleukin-2 Receptor alpha Subunit; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D016212:Transforming Growth Factor beta; D054353:Perforin; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D053804:Granzymes; D015232:Dinoprostone