Dendritic cells partially abrogate the regulatory activity of CD4+CD25+ T cells present in the human peripheral blood (original) (raw)
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CD4-mediated functional activation of human CD4+CD25+ regulatory T cells
European Journal of Immunology, 2007
Naturally occurring CD4 + CD25 + FoxP3 + regulatory T cells (CD25 + Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral selftolerance. The immune regulatory function of CD25 + Tregs depends upon their activation. We found that anti-CD4 antibodies activate the suppressive function of human CD25 + Tregs in a dose-dependent manner. We demonstrate that CD4-activated CD25 + Tregs suppress the proliferation of CD4 + and CD8 + T cells, their IL-2 and IFN-c production as well as the capacity of CD8 + T cells to re-express CD25. By contrast, anti-CD4 stimulation did not induce suppressive activity in conventional CD4 + T cells. These results identify CD4 as a trigger for the suppressive function of CD25 + Tregs and suggest a possible CD4-mediated exploitation of these cells.
International Immunology, 2007
CD4 1 CD25 1 regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4 1 CD25 1 Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the upregulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (g c) cytokines-IL-4, IL-7 and IL-15-had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the g c cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4 1 CD25 1 T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.
Expansion of CD4 + CD25 + Foxp3 + T cells by bone marrow-derived dendritic cells
Immunology, 2009
Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system and have a crucial role in T-lymphocyte activation and adaptive immunity initiation. However, DCs have also been implicated in maintaining immunological tolerance. In this study, we evaluated changes in the CD4+ CD25+ Foxp3+ T-cell population after co-culture of lymph node cells from BALB/c mice with syngeneic bone marrow-derived DCs. Our results showed an increase in CD4+ CD25+ Foxp3+ T cells after co-culture which occurred regardless of the activation state of DCs and the presence of allogeneic apoptotic cells; however, it was greater when DCs were immature and were pulsed with the alloantigen. Interestingly, syngeneic apoptotic thymocytes were not as efficient as allogeneic apoptotic cells in expanding the CD4+ CD25+ Foxp3+ T-cell population. In all experimental settings, DCs produced high amounts of transforming growth factor (TGF)-β. The presence of allogeneic apoptotic cells induced interleukin (IL)-2 production in immature and mature DC cultures. This cytokine was also detected in the supernatants under all experimental conditions and enhanced when immature DCs were pulsed with the alloantigen. CD4+ CD25+ Foxp3+ T-cell expansion during co-culture of lymph node cells with DCs strongly suggested that the presence of alloantigen enhanced the number of regulatory T cells (Tregs) in vitro. Our data also suggest a role for both TGF-β and IL-2 in the augmentation of the CD4+ CD25+ Foxp3+ population.
The Journal of Immunology, 2010
IL-10-differentiated dendritic cells (DC10) induce allergen tolerance in asthmatic mice, during which their lung Th2 effector T cells (Teffs) are displaced by activated CD4 + CD25 hi Foxp3 + T cells. Intestinal DCs promote oral tolerance by inducing Ag-naive T cells to differentiate into CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), but whether DCs can induce Teffs to differentiate into Tregs remains uncertain. In this study, we addressed this question in OVA-asthmatic mice that were treated with DC10. OVA-presenting DC10 treatment maximally activated lung Tregs in these animals at 3 wk posttreatment, as determined by upregulation of activation markers (ICOS, programmed cell death-1, glucocorticoid-induced TNFR-related protein, LAG3, and CTLA-4) and in functional assays. This in vitro regulatory activity was ‡90% reduced by treatment with anti-IL-10 but not anti-TGF-b Abs. In parallel cultures, OVA-but not house dust mite (HDM)-presenting DC10 induced 43% of CFSE-labeled CD25 2/lo Foxp3 2 Teffs from asthmatic OVA-TCR transgenic mice to differentiate into tolerogenic CD25 hi Foxp3 + Tregs. We recapitulated this in vivo using OVA-asthmatic mice that were coinjected with OVA-or HDM-presenting DC10 (i.p.) and CFSE-labeled CD4 + CD25-/lo Foxp3 2 Teffs (i.v.) from the lungs of asthmatic DO11.10 mice. From 7 to 21% of the activated (i.e., dividing) DO11.10 Teffs that were recovered from the lungs, lung-draining lymph nodes, or spleens of the OVA-DC10 recipients had differentiated into CD4 + CD25 hi Foxp3 + Tregs, whereas no CFSE-positive Tregs were recovered from the HDM-DC10-treated animals. These data indicate that DC10 treatments induce tolerance at least in part by inducing Teffs to differentiate into CD4 + CD25 hi Foxp3 + Tregs.
Clinical & Developmental Immunology, 2008
CD25 + CD4 + regulatory T cells suppress T cell activation and regulate multiple immune reactions in in vitro and in vivo studies. To define the regulatory function of human CD25 + CD4 + T cells at various stages of maturity, we investigated in detail the functional differences of CD25 + CD4 + T cells from thymocytes, cord blood (CB), and adult peripheral blood (APB). CB CD25 + CD4 + T cells displayed low-FOXP3 protein expression level and had no suppressive activity. In contrast, CD25 + CD4 + T cells from thymocytes or APB expressed high expression level of FOXP3 protein associated with significant suppressive activity. Although CB CD25 + CD4 + T cells exhibited no suppressive activity, striking suppressive activity was observed following expansion in culture associated with increased FOXP3 expression and a shift from the CD45RA + to the CD45RA − phenotype. These functional differences in CD25 + CD4 + T cells from Thy, CB, and APB hence suggest a pathway of maturation for Treg in the peripheral immune system.
CD4+CD25lowGITR+ cells: A novel human CD4+ T-cell population with regulatory activity
European Journal of Immunology, 2011
Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged-helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL-10 and TGF-b. Glucocorticoid-induced TNF receptor family-related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4 1 T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4 1 T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4 1 CD25 low GITR 1 ). These cells show Treg features as they express FOXP3, IL-10, TGF-b and are anergic but, as opposed to natural Tregs, express low levels of CTLA-4 and are CD127 high . CD4 1 CD25 low GITR 1 cells represent a low percentage of the CD4 1 T-cell population (0.32-1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4 1 CD25 low GITR 1 cells have relevant suppressive activity that depends on TGF-b. Moreover, an anti-GITR Ab inhibited their suppressive activity, as observed in CD4 1 CD25 1 murine Tregs. Taken together, these data indicate that human CD4 1 CD25 low GITR 1 cells represent a distinct Treg subpopulation.
2008
Although the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through binding and activation of the aryl hydrocarbon receptor (AhR), the subsequent biochemical and molecular changes that confer immune suppression are not well understood. Mice exposed to TCDD during an acute B6-into-B6D2F1 graft-vs-host response do not develop disease, and recently this has been shown to correlate with the generation of CD4 ؉ T cells that express CD25 and demonstrate in vitro suppressive function. The purpose of this study was to further characterize these CD4 ؉ cells (TCDD-CD4 ؉ cells) by comparing and contrasting them with both natural regulatory CD4 ؉ T cells (T-regs) and vehicle-treated cells. Cellular anergy, suppressive functions, and cytokine production were examined. We found that TCDD-CD4 ؉ cells actively proliferate in response to various stimuli but suppress IL-2 production and the proliferation of effector T cells. Like natural T-regs, TCDD-CD4 ؉ cells do not produce IL-2 and their suppressive function is contact dependent but abrogated by costimulation through glucocorticoid-induced TNFR (GITR). TCDD-CD4 ؉ cells also secrete significant amounts of IL-10 in response to both polyclonal and alloantigen stimuli. Several genes were significantly up-regulated in TCDD-CD4 ؉ cells including TGF-3, Blimp-1, and granzyme B, as well as genes associated with the IL12-Rb2 signaling pathway. TCDD-CD4 ؉ cells demonstrated an increased responsiveness to IL-12 as indicated by the phosphorylation levels of STAT4. Only 2% of TCDD-CD4 ؉ cells express Foxp3, suggesting that the AhR does not rely on Foxp3 for suppressive activity. The generation of CD4 ؉ cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs.
Journal of Experimental Medicine, 2000
The functional properties of dendritic cells (DCs) are strictly dependent on their maturational state. To analyze the influence of the maturational state of DCs on priming and differentiation of T cells, immature CD83 Ϫ and mature CD83 ϩ human DCs were used for stimulation of naive, allogeneic CD4 ϩ T cells. Repetitive stimulation with mature DCs resulted in a strong expansion of alloreactive T cells and the exclusive development of T helper type 1 (Th1) cells. In contrast, after repetitive stimulation with immature DCs the alloreactive T cells showed an irreversibly inhibited proliferation that could not be restored by restimulation with mature DCs or peripheral blood mononuclear cells, or by the addition of interleukin (IL)-2. Only stimulation of T cells with mature DCs resulted in an upregulation of CD154, CD69, and CD70, whereas T cells activated with immature DCs showed an early upregulation of the negative regulator cytotoxic T lymphocyte-associated molecule 4 (CTLA-4). These T cells lost their ability to produce interferon ␥ , IL-2, or IL-4 after several stimulations with immature DCs and differentiated into nonproliferating, IL-10-producing T cells. Furthermore, in coculture experiments these T cells inhibited the antigen-driven proliferation of Th1 cells in a contact-and dose-dependent, but antigen-nonspecific manner. These data show that immature and mature DCs induce different types of T cell responses: inflammatory Th1 cells are induced by mature DCs, and IL-10-producing T cell regulatory 1-like cells by immature DCs.