title: Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4+ regulatory T cells.
abstract: Dendritic cells (DC) have important functions in T cell immunity and T cell tolerance. Previously, it was believed that T cell unresponsiveness induced by immature DC (iDC) is caused by the absence of inflammatory signals in steady-state in vivo conditions and by the low expression levels of costimulatory molecules on iDC. However, a growing body of evidence now indicates that iDC can also actively maintain peripheral T cell tolerance by the induction and/or stimulation of regulatory T cell populations. In this study, we investigated the in vitro T cell stimulatory capacity of iDC and mature DC (mDC) and found that both DC types induced a significant increase in the number of transforming growth factor (TGF)-beta and interleukin (IL)-10 double-positive CD4(+) T cells within 1 week of autologous DC/T cell co-cultures. In iDC/T cell cultures, where antigen-specific T cell priming was significantly reduced as compared to mDC/T cell cultures, we demonstrated that the tolerogenic effect of iDC was mediated by soluble TGF-beta and IL-10 secreted by CD4(+)CD25(-)FOXP3(-) T cells. In addition, the suppressive capacity of CD4(+) T cells conditioned by iDC was transferable to already primed antigen-specific CD8(+) T cell cultures. In contrast, addition of CD4(+) T cells conditioned by mDC to primed antigen-specific CD8(+) T cells resulted in enhanced CD8(+) T cell responses, notwithstanding the presence of TGF-beta(+)/IL-10(+) T cells in the transferred fraction. In summary, we hypothesize that DC have an active role in inducing immunosuppressive cytokine-secreting regulatory T cells. We show that iDC-conditioned CD4(+) T cells are globally immunosuppressive, while mDC induce globally immunostimulatory CD4(+) T cells. Furthermore, TGF-beta(+)/IL-10(+) T cells are expanded by DC independent of their maturation status, but their suppressive function is dependent on immaturity of DC.
authors.affiliation: Vaccine and Infectious Disease Institute (VIDI) [corrected] Laboratory of Experimental Hematology, Faculty of Medicine, Antwerp University, Belgium. Natalie.Cools@uza.be
authors.forename: N
authors.initials: N
authors.lastname: Cools
authors.forename: V F I
authors.initials: VF
authors.lastname: Van Tendeloo
authors.forename: E L J M
authors.initials: EL
authors.lastname: Smits
authors.forename: M
authors.initials: M
authors.lastname: Lenjou
authors.forename: G
authors.initials: G
authors.lastname: Nijs
authors.forename: D R
authors.initials: DR
authors.lastname: Van Bockstaele
authors.forename: Z N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: P
authors.initials: P
authors.lastname: Ponsaerts
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D018189:Immunomagnetic Separation; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000276:immunology*; D018448:Models, Immunological; D009000:Monocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D016212:Transforming Growth Factor beta; D016753:Interleukin-10