IL-15 and cognate antigen successfully expand de novo-induced human antigen-specific regulatory CD4+ T cells that require antigen-specific activation for suppression.
An important prerequisite in using regulatory T cells for immunotherapy is their ex vivo expansion without loss of suppressor function. Human anergic regulatory T cells are expandable by Ag-specific stimulation in the presence of IL-2. IL-15, like IL-2, is a T cell growth factor that, in contrast to IL-2, stimulates survival of T cells. In this study, we examined whether IL-15 could be exploited as a superior growth factor of human CD4(+) anergic regulatory T cells that were generated by costimulation blockade. Next, IL-15, as compared with IL-2, was investigated with respect to expansion and function of these regulatory T cells. Optimal expansion required cognate allogeneic stimulation in the presence of exogenous IL-15. IL-15 resulted in enhanced survival that was paralleled by an increased number of Bcl-2-expressing cells. Moreover, IL-15 induced a distinct type of anergy characterized by hyperreactivity to IL-15, resulting in improved expansion. This is likely attributed to increased propensity of these cells to up-regulate both alpha- and gamma-chains of the IL-2 and IL-15 receptor. Notably, IL-15-expanded regulatory CD4(+) T cells suppressed both naive and memory T cells in a superior way. Immunosuppression required alloantigen-specific stimulation and appeared gamma-irradiation resistant and independent of IL-10, TGFbeta, or CTLA-4 interactions. These regulatory T cells were stable suppressors, mediating bystander suppression upon TCR stimulation, but leaving recall responses unaffected in the absence of cognate Ag. Finally, human naturally occurring regulatory CD4(+)CD25(+) T cells appeared important in generating regulatory T cells by costimulation blockade. In conclusion, IL-15-expanded, de novo-induced human anergic regulatory CD4(+) T cells are of interest in Ag-specific immunotherapy.
Koenen
Hans J P M
HJ
Department for Blood Transfusion and Transplantation Immunology, University Medical Center, Nijmegen, The Netherlands. H.Koenen@abti.umcn.nl
Fasse
Esther
E
Joosten
Irma
I
D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000502:physiology; D051940:B7-2 Antigen; D024201:Bystander Effect / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000502:physiology; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase / Q000276:immunology; D007424:Intracellular Fluid / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013194:Staining and Labeling; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D019409:Interleukin-15; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10