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Project description:Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.
2023-12-08 | GSE249186 | GEO
Project description:Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are under clinical investigation for treating autoimmune and inflammatory diseases. We previously described an Fc-fused CD25-biased IL-2 mutein (Fc.IL-2 mutein) that promotes TR expansion and prevents the onset of autoimmune diabetes in non-obese diabetic (NOD) mice; however, the effects of this treatment on TR function in vivo are unclear. Here we show that Fc.IL-2 mutein treatment induces an activated Foxp3+ TR population characterized by elevated proliferation, a unique transcriptional program associated with Stat5- and TCR-dependent gene modules, and high levels of the immunosuppressive molecules IL-10 and CTLA-4. Increased IL-10 receptor signaling limits the upregulation of surface MHC class II expression during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis leads to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to Tregs. In NOD mice, Fc.IL-2 mutein treatment resulted in TR-mediated regulation of cDCs in the inflamed pancreas and draining lymph nodes accompanied by an increase in anergic T cells. Thus, we demonstrate that IL-2 mutein-expanded TR cells have enhanced functional properties and potently act to restrict cDC function in the target tissue and at the site of autoimmune induction, offering promising prospects for targeted immunotherapy.
2023-12-08 | GSE249481 | GEO
Project description:Regulatory B cells (Bregs) suppress and reduce autoimmune pathology. However, given the variety of Breg subsets, the role of Bregs in the pathogenesis of type 1 diabetes is still unclear. Here, we dissect this fundamental mechanism. We show that natural protection from type 1 diabetes in nonobese diabetic (NOD) mice is associated with increased numbers of IL-10-producing B cells, while development of type 1 diabetes in NOD mice occurs in animals with compromised IL-10 production by B cells. However, B cells from diabetic mice regain IL-10 function if activated by the innate immune receptor TLR4 and can suppress insulin-specific CD8 T cells in a dendritic cell (DC)-dependent, IL-10-mediated fashion. Suppression of CD8 T cells is reliant on B-cell contact with DCs. This cell contact results in deactivation of DCs, inducing a tolerogenic state, which in turn can regulate pathogenic CD8 T cells. Our findings emphasize the importance of DC-Breg interactions during the development of type 1 diabetes.
| S-EPMC7395736 | biostudies-literature
Project description:CD40 expressed on stimulatory dendritic cells (DC) provides an important accessory signal for induction of effector T cell responses. It is also expressed at lower levels on regulatory DC (DCreg), but there is little evidence that CD40 signaling contributes to the tolerogenic activity of these cells. Indeed, CD40 silencing within DCreg has been reported to induce T cell tolerance in multiple disease models, suggesting that CD40 is superfluous to DC-induced tolerance. We critically assessed whether CD40 does have a role in tolerance induced by IL-10-differentiated DC (DC10) by using DC10 generating from the bone marrow of wild-type (w.t.) or CD40-/- donor mice, or IL-10-complemented CD40-/- DC10 to treat asthmatic mice. Wild-type DC10 ablated the OVA-asthma phenotype via induction of Foxp3+ Treg responses, but CD40-/- DC10 had no discernible effects on primary facets of the phenotype (e.g., IL-5, IL-9, IL-13 levels, IgE & IgG1 antibodies; p>0.05) and were ≤40% effective in reversal of others. Foxp3+ T cells from the lungs of CD40-/- DC10-treated mice expressed reduced levels of a panel of six Treg-specific activation markers relative to Treg from w.t. DC10-treated mice. Coculture with effector T cells from asthmatic mice induced a marked upregulation of cell surface CD40 on w.t. DC10. While untreated CD40-/- and w.t. DC10 secreted equally low levels of IL-10, stimulation of w.t. DC10 with anti-CD40 for 72 h increased their expression of IL-10 by ≈250%, with no parallel induction of IL-12. Complementing IL-10 expression in CD40-/- DC10 by IL-10 mRNA transfection fully restored the cells' abilities to suppress the asthma phenotype. In summary, CD40 signaling in DC10 contributes importantly to their expression of IL-10 and to a robust induction of tolerance, including activation of induced Treg.
| S-EPMC8016274 | biostudies-literature
Project description:Mesenchymal stromal cell-like (MSCl) cells generated from human embryonic stem cells are considered to be an eligible cell line to model the immunomodulatory behavior of mesenchymal stromal cells (MSCs) in vitro. Dendritic cells (DCs) are essential players in the maintenance and restoration of the sensitive balance between tolerance and immunity. Here, the effects of MSCl cells on the in vitro differentiation of human monocytes into DCs were investigated. MSCl cells promote the differentiation of CTLA-4 expressing DCs via the production of all-trans retinoic acid (ATRA) functioning as a ligand of RARα, a key nuclear receptor in DC development. These semi-matured DCs exhibit an ability to activate allogeneic, naive T cells and polarize them into IL-10 + IL-17 + double-positive T helper cells in a CTLA-4-dependent manner. Mapping the molecular mechanisms of MSC-mediated indirect modulation of DC differentiation may help to expand MSCs' clinical application in cell-free therapies.
| S-EPMC8027231 | biostudies-literature
Project description:Foxp3(+) T regulatory cells (Tregs) are critically important for the maintenance of immunological tolerance, immune homeostasis, and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Tregs with CD80/CD86 on the DCs resulting in downregulation of CD80/CD86 expression and a decrease in costimulation. We have re-examined the effects of Tregs on mouse DC function in a model in which Ag-specific, induced Tregs (iTregs) are cocultured with DCs in the absence of T effector cells. iTreg-treated DCs are markedly defective in their capacity to activate naive T cells. iTregs from CTLA-4-deficient mice failed to induce downregulation of CD80/CD86, but DCs treated with CTLA-4-deficient iTregs still exhibited impaired capacity to activate naive T cells. The iTreg-induced defect in DC function could be completely reversed by anti-IL-10, and IL-10-deficient iTregs failed to downregulate DC function. iTreg-treated DCs expressed high levels of MARCH1, an E3 ubiquitin ligase, recently found to degrade CD86 and MHC class II on the DCs and expressed lower levels of CD83, a molecule involved in neutralizing the function of MARCH1. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTregs. Taken together, these studies demonstrate that a major suppressive mechanism of DC function by iTregs is secondary to the effects of IL-10 on MARCH1 and CD83 expression.
| S-EPMC3858537 | biostudies-literature
Project description:Regulatory T cells (T(reg)) are believed to suppress conventional T cell (T(conv)) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which T(reg) and T(conv) are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural T(reg), increases substantially following contact with T(conv). Surprisingly, T(reg) were able to mediate potent suppression of T(conv) across a permeable membrane when placed in direct contact with T(conv) in the upper chamber of a Transwell plate. Suppression was IL-35 and IL-10 dependent, and T(conv) activation was required for maximal potentiation of T(reg) suppression. These data suggest that it is the induction of suppression, rather than the function of T(reg) that is obligatorily contact dependent.
| S-EPMC2698997 | biostudies-literature
Project description:Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell-mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10-producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10-producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.
| S-EPMC2118437 | biostudies-literature
Project description:IL-10 produced by dendritic cells (DC) can limit or terminate ongoing inflammatory responses by inhibiting the proinflammatory cytokine production. Currently, the molecular mechanism by which IL-10 suppresses cytokine production is still ill-defined. In this study, we showed that IL-10 produced by DC dampens myeloid differentiation factor (MyD)88-dependent, but not MyD88-independent signaling. At the molecular level, IL-10 induces ubiquitination and subsequent protein degradation of MyD88-dependent signaling molecules, including IL-1 receptor-associated kinase 4 and TNF-receptor associated factor 6. Protein degradation by IL-10 was associated with decreased phosphorylation of p38, JNK, and IKK. All of these events were prevented by either blocking IL-10 receptor signaling or inhibiting proteasome degradation. IL-10 induced LPS hyporesponsiveness using the same mechanisms, i.e., ubiquitination and protein degradation. Thus, a previously undescribed regulatory mechanism by which IL-10-mediated protein degradation contributes to the inhibition of inflammatory cytokine production and endotoxin tolerance in DC.
| S-EPMC2775313 | biostudies-literature
Project description:Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo.Mice were treated with anti-CTLA-4 monoclonal antibody (mAb) (UC10-4F10) at the time of immunisation or colonic instillation of trinitrobenzene sulfonic acid (TNBS). The cytokines produced by lymph node cells after in vitro antigenic stimulation and the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10 (IL-10) were tested, and the survival of mice was monitored.Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4(+) regulatory T cells which expressed high levels of ICOS (inducible co-stimulator), secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOS(high) Foxp3(+) T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO.These observations emphasise the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.
| S-EPMC2917097 | biostudies-literature