Enhancement of antigen-specific Treg vaccination in vivo.
Ontology highlight
ABSTRACT:
SUBMITTER: Daniel C
PROVIDER: S-EPMC2941325 | biostudies-other | 2010 Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are of special interest in immunology because of their potent inhibitory function. Many fundamental aspects of Tregs, including their antigenic profile, development and peripheral homeostasis, remain highly controversial. Here, we propose a Treg-centered antigen-non-specific immunoregulation model focused on the T-cell system, particularly on CD4(+) T cells. The T-cell pool consists of naive T cells (Tnais), Tregs and effector T cells (Teffs). Regardless of antigen specificity, the ratio of the activated T-cell subsets (Treg/Teff/Tnai) and their temporal and spatial uniformity dictate the differentiation of Tnais. Activated Tregs inhibit the activation, proliferation, induction and activity of Teffs; in contrast, activated Teffs inhibit the induction of Tregs from Tnais but cooperate with Treg-specific antigens to promote the proliferation and activity of Tregs. In many cases, these interactions are antigen-non-specific, whereas the activation of both Tregs and Teffs is antigen-specific. Memory T-cell subsets are essential for the maintenance of adaptive immune responses, but the antigen-non-specific interactions among T-cell subsets may be more important during the establishment of the adaptive immune system to a newly encountered antigen. This is especially important when new and memory antigens are presented closely-both temporally and spatially-to T cells, because there are always baseline levels of activated Tregs, which are usually higher than levels of memory T cells for new antigens. Based on this hypothesis, we further infer that, under physiological conditions, Tregs in lymph nodes mainly recognize antigens frequently released from draining tissues, and that these self-reactive Tregs are commonly involved in the establishment of adaptive immunity to new antigens and in the feedback control of excessive responses to pathogens.
| S-EPMC3094156 | biostudies-other
Project description:T cell upregulation of B7 molecules CD80 and CD86 limits T cell expansion in immunodeficient hosts; however, the relative roles of CD80 separate from CD86 on CD4 versus CD8 T cells in a normal immune system are not clear. To address this question, we used the parent-into-F1 (P?F1) murine model of graft-versus-host disease and transferred optimal and suboptimal doses of CD80 and/or CD86 knockout (KO) T cells into normal F1 hosts. Enhanced elimination of host B cells by KO T cells was observed only at suboptimal donor cell doses and was greatest for CD80 KO?F1 mice. Wild-type donor cells exhibited peak CD80 upregulation at day 10; CD80 KO donor cells exhibited greater peak (day 10) donor T cell proliferation and CD8 T cell effector CTL numbers versus wild-type?F1 mice. Fas or programmed cell death-1 upregulation was normal as was homeostatic contraction of CD80 KO donor cells from days 12-14. Mixing studies demonstrated that maximal host cell elimination was seen when both CD4 and CD8 T cells were CD80 deficient. These results indicate an important role for CD80 upregulation on Ag-activated CD4 and CD8 T cells in limiting expansion of CD8 CTL effectors as part of a normal immune response. Our results support further studies of therapeutic targeting of CD80 in conditions characterized by suboptimal CD8 effector responses.
| S-EPMC3226733 | biostudies-literature
Project description:Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo. .
| S-EPMC4794126 | biostudies-literature
Project description:Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
| S-EPMC10019135 | biostudies-literature
Project description:Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD). One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg)- Immunoglobulin A (IgA) pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB) via the A2 linker of CT. Both dendritic cells (DCs) and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA) signaling but was inhibited by neutralization of TGF-?. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR) signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.
| S-EPMC5531474 | biostudies-literature
Project description:BackgroundThe function of T helper cell subsets in vivo depends on their location, and one hallmark of T cell differentiation is the sequential regulation of migration-inducing chemokine receptor expression. CC-chemokine receptor 6 (CCR6) is a trait of tissue-homing effector T cells and has recently been described as a receptor on T helper type 17 (Th17) cells. Th17 cells are associated with autoimmunity and the defence against certain infections. Although, the polarization of Th cells into Th17 cells has been studied extensively in vitro, the development of those cells during the physiological immune response is still elusive.Methodology/principal findingsWe analysed the development and functionality of Th17 cells in immune-competent mice during an ongoing immune response. In naïve and vaccinated animals CCR6(+) Th cells produce IL-17. The robust homeostatic proliferation and the presence of activation markers on CCR6(+) Th cells indicate their activated status. Vaccination induces antigen-specific CCR6(+) Th17 cells that respond to in vitro re-stimulation with cytokine production and proliferation. Furthermore, depletion of CCR6(+) Th cells from donor leukocytes prevents recipients from severe disease in experimental autoimmune encephalomyelitis, a model for multiple sclerosis in mice.Conclusions/significanceIn conclusion, we defined CCR6 as a specific marker for functional antigen-specific Th17 cells during the immune response. Since IL-17 production reaches the highest levels during the immediate early phase of the immune response and the activation of Th17 cells precedes the Th1 cell differentiation we tent to speculate that this particular Th cell subset may represent a first line effector Th cell subpopulation. Interference with the activation of this Th cell subtype provides an interesting strategy to prevent autoimmunity as well as to establish protective immunity against infections.
| S-EPMC2491584 | biostudies-literature
Project description:Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor ? (TGF?) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA).CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry.Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice.These findings provide evidence that transferred TGF?-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.
| S-EPMC4364395 | biostudies-literature
Project description:We, and others, have reported that in the HIV-negative settings, regulatory CD4+CD25highFoxP3+ T cells (Treg) exert differential effects on CD8 subsets, and maintain the memory / effector CD8+ T cells balance, at least in part through the PD-1/PD-L1 pathway. Here we investigated Treg-mediated effects on CD8 responses in chronic HIV infection. As compared to Treg from HIV negative controls (Treg/HIV-), we show that Treg from HIV infected patients (Treg/HIV+) did not significantly inhibit polyclonal autologous CD8+ T cell function indicating either a defect in the suppressive capacity of Treg/HIV+ or a lack of sensitivity of effector T cells in HIV infection. Results showed that Treg/HIV+ inhibited significantly the IFN-γ expression of autologous CD8+ T cells stimulated with recall CMV/EBV/Flu (CEF) antigens, but did not inhibit HIV-Gag-specific CD8+ T cells. In cross-over cultures, we show that Treg/HIV- inhibited significantly the differentiation of either CEF- or Gag-specific CD8+ T cells from HIV infected patients. The expression of PD-1 and PD-L1 was higher on Gag-specific CD8+ T cells as compared to CEF-specific CD8+ T cells, and the expression of these markers did not change significantly after Treg depletion or co-culture with Treg/HIV-, unlike on CEF-specific CD8+ T cells. In summary, we show a defect of Treg/HIV+ in modulating both the differentiation and the expression of PD-1/PD-L1 molecules on HIV-specific CD8 T cells. Our results strongly suggest that this particular defect of Treg might contribute to the exhaustion of HIV-specific T cell responses.
| S-EPMC5102588 | biostudies-literature
Project description:We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset-promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg. Our data implies that while HDAC6 and Bcl6 are important regulators of Treg plasticity, GATA3 determine the fate of plastic Tregby controlling whether it will convert in to either Th1-Treg or APC-T-reg. Our results have provided novel insights on Treg plasticity into APC-Treg and Th1-Treg, and new therapeutic targets in metabolic diseases, autoimmune diseases, and inflammatory disorders.
| S-EPMC5790774 | biostudies-other
Project description:Adoptive transfer of regulatory T cells (Treg) can induce transplant tolerance in preclinical models by suppressing alloantigen-directed inflammatory responses; clinical translation was so far hampered by the low abundance of Treg with allo-specificity in the peripheral blood. In this situation, ex vivo engineering of Treg with a T-cell receptor (TCR) or chimeric antigen receptor (CAR) provides a cell population with predefined specificity that can be amplified and administered to the patient. In contrast to TCR-engineered Treg, CAR Treg can be redirected toward a broad panel of targets in an HLA-unrestricted fashion' making these cells attractive to provide antigen-specific tolerance toward the transplanted organ. In preclinical models, CAR Treg accumulate and amplify at the targeted transplant, maintain their differentiated phenotype, and execute immune repression more vigorously than polyclonal Treg. With that, CAR Treg are providing hope in establishing allospecific, localized immune tolerance in the long term' and the first clinical trials administering CAR Treg for the treatment of transplant rejection are initiated. Here, we review the current platforms for developing and manufacturing alloantigen-specific CAR Treg and discuss the therapeutic potential and current hurdles in translating CAR Treg into clinical exploration.
| S-EPMC9746345 | biostudies-literature