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Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.

Autoimmune diseases result from imbalances in the immune system and disturbances in the mechanisms of immune tolerance. T-regulatory cells (Treg) are key factors in the formation of immune tolerance. Tregs modulate immune responses and repair processes, controlling the innate and adaptive immune system. The use of Tregs in the treatment of autoimmune diseases began with the manipulation of endogenous Tregs using immunomodulatory drugs. Then, a method of adoptive transfer of Tregs grown in vitro was developed. Adoptive transfer of Tregs includes polyclonal Tregs with non-specific effects and antigen-specific Tregs in the form of CAR-Treg and TCR-Treg. This review discusses non-specific and antigen-specific approaches to the use of Tregs, their advantages, disadvantages, gaps in development, and future prospects.

Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.

: Neuroinflammation is a primary feature of Alzheimer's disease (AD), for which an increasing number of drugs have been specifically developed. The present study aimed to define the therapeutic impact of a specific subpopulation of T cells that can suppress excessive inflammation in various immune and inflammatory disorders, namely, CD4 CD25 Foxp3 regulatory T cells (Tregs). : To generate Aβ antigen-specific Tregs (Aβ Tregs), Aβ 1-42 peptide was applied and subsequent splenocyte culture. After isolating Tregs by magnetic bead based purification method, Aβ Tregs were adoptively transferred into 3xTg-AD mice via tail vein injection. Therapeutic efficacy was confirmed with behavior test, Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining (IHC). suppression assay was performed to evaluate the suppressive activity of Aβ Tregs using flow cytometry. Thy1.1 Treg trafficking and distribution was analyzed to explore the infused Tregs migration into specific organs in an antigen-driven manner in AD mice. We further assessed cerebral glucose metabolism using F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of Aβ Tregs toward Aβ activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay. : We showed that Aβ-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of Aβ Tregs was enough to induce amelioration of cognitive impairments, Aβ accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, Aβ-specific Tregs effectively inhibited inflammation in primary microglia induced by Aβ exposure. It may indicate bystander suppression in which Aβ-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration. : The administration of Aβ antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.

Background Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCR A β ). The TCR Ab were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR Aβ (TCR Aβ -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer’s disease. Methods TCR A β -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR Ab identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR Aβ -Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. Results TCR Aβ -Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR Aβ -Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18 F-fluorodeoxyglucose radiolabeled TCR Aβ -Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions TCR Aβ -Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD. Graphical Abstract

Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases had long been immunosuppressive agents until the advent of immunomodulatory biologic drugs, which aimed at blocking inflammatory mediators, including proinflammatory cytokines. At the frontier of these biologic drugs are TNF-α blockers. These therapies inhibit the proinflammatory action of TNF-α in common autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn’s disease. TNF-α blockade quickly became the “standard of care” for these autoimmune diseases due to their effectiveness in controlling disease and decreasing patient’s adverse risk profiles compared to broad-spectrum immunosuppressive agents. However, anti-TNF-α therapies have limitations, including known adverse safety risk, loss of therapeutic efficacy due to drug resistance, and lack of efficacy in numerous autoimmune diseases, including multiple sclerosis. The next wave of truly transformative therapeutics should aspire to provide a cure by selectively suppressing pathogenic autoantigen-specific immune responses while leaving the rest of the immune system intact to control infectious diseases and malignancies. In this review, we will focus on three main areas of active research in immune tolerance. First, tolerogenic vaccines aiming at robust, lasting autoantigen-specific immune tolerance. Second, T cell therapies using Tregs (either polyclonal, antigen-specific, or genetically engineered to express chimeric antigen receptors) to establish active dominant immune tolerance or T cells (engineered to express chimeric antigen receptors) to delete pathogenic immune cells. Third, IL-2 therapies aiming at expanding immunosuppressive regulatory T cells in vivo .

The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. or manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Current treatments, including insulin replacement therapy and various immunotherapies, often modulate but fail to permanently halt the underlying autoimmune process or restore β-cell function. In this review, we examine T cell receptor (TCR)-based treatment strategies for T1DM. We focus on two main approaches: selective elimination of pathogenic autoreactive T cell clones and induction of immune tolerance using TCR-modified regulatory T cells (TCR-Tregs). We describe key islet autoantigens, including post-translationally modified neoantigens such as fusion insulin peptides, which are crucial for identifying pathogenic TCRs. Next, we will review methodologies for TCR detection and TCR-Treg generation, highlighting their mechanisms of action and impact on various immune cells, including dendritic cells, B cells, and macrophages. We will also examine the potential of CD8 T cell regulatory cells (CD8 Tregs). Finally, we will discuss the future of TCR-based therapy, emphasizing the need to optimize TCR affinity, ensure Tregs' stability, and develop combination therapies. TCR-based therapy represents a revolutionary approach to restoring immune tolerance in T1DM, providing high specificity and reducing the risk of systemic immuno-suppression compared to traditional treatments.

Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.

Background Multiple sclerosis (MS) is an immune-mediated disorder characterized by demyelination, axonal damage, and neurodegeneration, leading to neurological disability in patients. It is considered a prototypic antigen-specific autoimmune disease, and therefore is a strong candidate for therapies aimed at restoring immune tolerance to self-antigens. However, the development of effective antigen-specific tolerization remains an important unmet medical need. In the present study, we administered phosphatidylserine (PS) liposomes, mimicking apoptotic bodies, containing a myelin antigen [35–55 myelin oligodendrocyte glycoprotein (MOG 35 − 55 ) peptide] in the MOG 35 − 55 -induced experimental autoimmune encephalomyelitis (EAE), as a therapeutic strategy for the treatment of MS. Methods MOG PS liposomes or empty PS liposomes were administered in a single administration before or after the appearance of EAE neurological symptoms. Intraperitoneal, intranasal, intradermal and intravenous administration routes were used. For mechanistic studies, peripheral T and B cell subpopulations of treated EAE mice were studied by flow cytometry. In addition, EAE mice treated with MOG PS liposomes received blocking antibodies to deplete Treg, B cells, and immunomodulatory mediators IL-10 and TGF-β. The efficacy of the therapy was compared with daily administration of fingolimod. Results We demonstrated the therapeutic efficacy of the MOG-loaded PS liposomes when administered intraperitoneally before onset, and the mechanism of action of MOG-loaded PS liposomes involved Treg and B cells, since blocking these populations and their related molecules IL-10 and TGF-β, abrogated the tolerogenic effect of the therapy. We also demonstrated the therapeutic efficacy of the MOG-loaded PS liposomes when administered intraperitoneally after appearance of EAE neurological signs. Alternative routes of administration such as intravenous and intradermal, which are more suited for translation in clinical trials, were found to be efficacious before and after appearance of EAE neurological signs. Intravenous administration of MOG-loaded PS liposomes in established EAE reduced dendritic cell activation, decreased inflammatory cytokine secretion, induced T cell exhaustion and expanded regulatory B cells (Breg) and CD39 + CD4 + FoxP3 + T cells. Conclusions Our findings indicate that antigen-specific therapy with PS liposomes mimicking apoptotic bodies downregulates the MOG-specific inflammatory immune response and expands Breg and Treg cells, offering a safe, versatile, and easily applicable approach that strongly supports its potential for near-future clinical translation in MS.