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PubMed2026

The future of TCR-Treg therapies is renewables.

Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.

Humans↗
PubMed2003

Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity.

CD4+CD25+ regulatory T cells (Treg cells) prevent T cell-mediated autoimmune diseases in rodents. To develop a functional Treg assay for human blood cells, we used FACS- or bead-sorted CD4+CD25+ T cells from healthy donors to inhibit anti-CD3/CD28 activation of CD4+CD25- indicator T cells. The data clearly demonstrated classical Treg suppression of CD4+CD25- indicator cells by both CD4+CD25(+high) and CD4+CD25(+low) T cells obtained by FACS or magnetic bead sorting. Suppressive activity was found in either CD45RO- (naive) or CD45RO+ (memory) subpopulations, was independent of the TCR signal strength, required cell-cell contact, and was reversible by interleukin-2 (IL-2). Of general interest is that a wider sampling of 27 healthy donors revealed an age- but not gender-dependent loss of suppressive activity in the CD4+CD25+ population. The presence or absence of suppressive activity in CD4+CD25+ T cells from a given donor could be demonstrated consistently over time, and lack of suppression was not due to method of sorting, strength of signal, or sensitivity of indicator cells. Phenotypic markers did not differ on CD4+CD25+ T cells tested ex vivo from suppressive vs. nonsuppressive donors, although, upon activation in vitro, suppressive CD4+CD25+ T cells had significantly higher expression of both CTLA-4 and GITR than CD4+CD25- T cells from the same donors. Moreover, antibody neutralization of CTLA-4, GITR, IL-10, or IL-17 completely reversed Treg-induced suppression. Our results are highly consistent with those reported for murine Treg cells and are the first to demonstrate that suppressive activity of human CD4+CD25+ T cells declines with age.

Adult↗
PubMed2006

CD4+CD25+ Tregs and NKT cells: regulators regulating regulators.

CD4+CD25+ regulatory T cells (Tregs) and natural killer T (NKT) cells are two populations of T lymphocytes that can independently regulate adaptive and innate immune responses. Although most studies have investigated the regulatory properties of these T-cell subsets independently of each other, recent reports have provided evidence for cross-talk between Tregs and NKT cells, and, consequently, the immunoregulatory networks are seen in a new perspective. Activated NKT cells seem to modulate quantitatively and qualitatively Treg function through IL-2-dependent mechanisms, whereas Tregs can suppress the proliferation, cytokine release and cytotoxic activity of NKT cells by cell-contact-dependent mechanisms. Importantly, Tregs and NKT cells share crucial signaling pathways that could be responsible for their concerted responses. The advances in our understanding of the interactions between distinct subsets of regulatory T cells in autoimmunity might unveil new methods for harnessing these cells with immunotherapeutic properties.

Animals↗
PubMed2004

Homeostatic control of immunity by TCR peptide-specific Tregs.

Regulation of the immune response is a multifaceted process involving lymphocytes that function to maintain both self tolerance as well as homeostasis following productive immunity against microbes. There are 2 broad categories of Tregs that function in different immunological settings depending upon the context of antigen exposure and the nature of the inflammatory response. During massive inflammatory conditions such as microbial exposure in the gut or tissue transplantation, regulatory CD4+CD25+ Tregs broadly suppress priming and/or expansion of polyclonal autoreactive responses nonspecifically. In other immune settings where initially a limited repertoire of antigen-reactive T cells is activated and expanded, TCR-specific negative feedback mechanisms are able to achieve a fine homeostatic balance. Here I will describe experimental evidence for the existence of a Treg population specific for determinants that are derived from the TCR and are expressed by expanding myelin basic protein-reactive T cells mediating experimental autoimmune encephalomyelitis, an animal prototype for multiple sclerosis. These mechanisms ensure induction of effective but appropriately limited responses against foreign antigens while preventing autoreactivity from inflicting escalating damage. In contrast to CD25+ Tregs, which are most efficient at suppressing priming or activation, these specific Tregs are most efficient in controlling T cells following their activation.

Animals↗
PubMed2005

A peripheral circulating compartment of natural naive CD4 Tregs.

CD4CD25 Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4CD25 Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4CD25 Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25 T cells. Here we show that analysis of CD25 expression in human circulating CD4 T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25CCR7CD62LCTLA-4FOXP3 cells contained in the CD45RA/RO naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4 population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact-mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.

Adult↗
PubMed2005

Oral tolerance in the absence of naturally occurring Tregs.

Mucosal tolerance prevents pathological reactions against environmental and food antigens, and its failure results in exacerbated inflammation typical of allergies and asthma. One of the proposed mechanisms of oral tolerance is the induction of Tregs. Using a mouse model of hyper-IgE and asthma, we found that oral tolerance could be effectively induced in the absence of naturally occurring thymus-derived Tregs. Oral antigen administration prior to i.p. immunization prevented effector/memory Th2 cell development, germinal center formation, class switching to IgE, and lung inflammation. Oral exposure to antigen induced development of antigen-specific CD4CD25Foxp3CD45RB cells that were anergic and displayed suppressive activity in vivo and in vitro. Oral tolerance to the Th2 allergic response was in large part dependent on TGF-beta and independent of IL-10. Interestingly, Tregs were also induced by single i.p. immunization with antigen and adjuvant. However, unlike oral administration of antigen, which induced Tregs but not effector T cells, i.p. immunization led to the simultaneous induction of Tregs and effector Th2 cells displaying the same antigen specificity.

Administration, Oral↗
PubMed2006

[Isolation, identification and functional characterization of human CD4+ CD25+ Treg cells from human peripheral blood].

AIM: To isolate CD4(+) CD25(+) Treg cells from human peripheral blood, and study their functional characteristics. METHODS: The expressions of Foxp3 in human CD4(+) CD25(+) Treg cells were test by RT-PCR. The regulatory properties of CD4(+) CD25(+) Treg cells were assessed by co-culturing with CD4(+) CD25(-) T cells and CD8(+) T cells, or adding exogenous IL-2. The detection of intracellular cytokine production of IL-4, IL-10 and IFN-gamma was done by flow cytometry. RESULTS: CD4(+) CD25(+) Treg cells highly expressed Foxp3 and mainly synthesized IL-10 that suppressed the proliferation of CD4(+) CD25(-) T and CD8(+) T cells. Its suppressive function was reversed by high concentration of IL-2 and (or) IL-4. CONCLUSION: CD4(+) CD25(+) Treg cells exhibited a subpopulation of immunoregulatory T cells with suppressive function, which could be reversed by high concentration of IL-2.

Blood Cells↗
PubMed2006

Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.

Estrogen (E2)-induced immunomodulation involves dual effects on antigen-presenting cells (APC) and CD4(+)CD25(+) regulatory T cells (Treg) but not a direct effect on effector T cells. In this report, we further investigated the effects of E2 on APC and Treg function. We found that E2 treatment in vivo strongly reduced recovery of APC from the peritoneal cavity and inhibited induction of the inflammatory cytokines interleukin (IL)-12 and interferon-gamma but enhanced secretion of IL-10. Moreover, E2-conditioned bone marrow-derived dendritic cells (BM-DC) could both enhance Treg activity and directly inhibit responder T cells in the absence of Treg cells. We examined whether this E2-induced inhibitory activity of BM-DC might involve costimulation through the recently described PD-1 pathway. Both E2 and pregnancy markedly enhanced PD-1 expression in several types of APC, including macrophages, B cells, and especially dendritic cells (DC). Similarly to E2-induced enhancement of FoxP3 expression and experimental autoimmune encephalomyelitis protection, E2-induced enhancement of PD-1(+) cells was also mediated through estrogen receptor alpha (Esr1) in DC and macrophages but not in B cells. Based on antibody inhibition studies, PD-1 interaction with its ligands, PDL-1 and especially PDL-2, could mediate either positive or negative regulatory signaling in both mature and immature E2-conditioned DC, depending, respectively, on a relatively high (10:1) or low (1:1) ratio of T cells:BM-DC. These novel findings indicate that E2-induced immunomodulation is mediated in part through potentiation in BM-DC of the PD-1 costimulatory pathway.

Animals↗
PubMed2002

Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals.

Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the pancreatic lymph nodes and islets but not other lymph nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.

Animals↗
PubMed2005

A tax on luxury: HTLV-I infection of CD4+CD25+ Tregs.

Almost a quarter of a century ago, Oldstone and colleagues proposed that infection of cells by noncytopathic viruses may lead to an alteration of the cells' ability to produce certain products or perform certain tasks, i.e., inhibition of "luxury function." In this issue of the JCI, this topic has been revisited by Yamano et al., who demonstrate that human T cell lymphotropic virus type I (HTLV-I) infection of CD4(+)CD25(+) Tregs in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) results in a decrease in FOXP3 mRNA and protein expression. This leads to the inability of HTLV-I-infected CD4(+)CD25(+) Tregs to inhibit the proliferation of CD4(+)CD25(-) Tregs, due to the effect of the HTLV-I tax gene. Defects in the Treg population could be responsible for the large numbers of virus-specific T cells and occurrence of lymphoproliferation and inflammatory autoimmune disease in HAM/TSP patients.

CD4-Positive T-Lymphocytes↗
PubMed2006

Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs.

Safe induction of autoantigen-specific long-term tolerance is the "holy grail" for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3epsilon-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25(+)Foxp3(+) and insulin-specific Tregs producing IL-10, TGF-beta, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.

Administration, Intranasal↗
PubMed2005

TCR peptide vaccination in multiple sclerosis: boosting a deficient natural regulatory network that may involve TCR-specific CD4+CD25+ Treg cells.

Vaccination with self peptides contained within T cell receptor (TCR) chains, expressed by pathogenic Th1 cells can induce a second set of regulatory T cells that can reverse paralysis in rodents with experimental encephalomyelitis, and similarly, may have the potential to regulate myelin-reactive Th1 cells in patients with multiple sclerosis (MS). In this review, we discuss our recent discovery that TCR-reactive T cells generally possess classical inhibitory activity associated with Treg cells. CD4+CD25+ TCR-reactive T cells can inhibit CD4+CD25- indicator cells stimulated with anti-CD3/anti-CD28 antibody in a dose-dependent and cell-contact-dependent manner. Additionally, CD4+CD25+ T cells from blood of healthy control donors have significant responses to a pool of discriminatory TCR peptides, including BV10S1P, BV19S20, BV13S7, BV12S2A2T, BV11S1A1T, BV21S3A1T, AV15S1, and BV12S1A1N1. Patients with MS have varying degrees of deficient responses to TCR peptides, and by association, a defect in Treg cell function as well. TCR peptide vaccination using a new tripeptide mixture emulsified in IFA produced strong T cell responses in 100% of MS recipients, a dramatic improvement over previous vaccines given i.d. in saline that induced TCR-reactive T cell responses in about 50% of recipients. Responders to vaccination had a tendency towards reduced MRI lesions, and an early indication of enhanced Treg activity mediated by TCR-reactive T cells that could provide suppression of target as well as bystander T cells. These data provide a strong foundation for future TCR vaccination studies that will critically test the ability of the tripeptide mixture to induce significantly enhanced Treg activity and possible clinical and MRI benefits in vivo.

Animals↗
PubMed2006

DCs and cytokines cooperate for the induction of tregs.

Regulatory T cells (Treg) in broader terms consist of different subsets of T cells that are characterized by their ability to suppress proliferation of conventional effector T cells by various means. To date, three main groups of Treg can de distinguished, mainly by their functional properties (for review see Jonuleit and Schmitt 2003) Briefly, T regulatory (Tr)-1 cells as well as T helper (Th)-3 T cells express common T cell markers such as CD4 and are characterized by secretion of IL-10 and TGF-beta, which provides a means by which proliferation of conventional CD4+ cells is blocked. In contrast, genuine Treg that are characterized by their expression of CD25 block T cell proliferation by an unknown cell-to-cell contact-dependent mechanism. However, there are many overlapping features shared by the different subtypes of regulatory T cell and the common denominator is the production of regulatory cytokines such as IL-10 and TGF-beta.

Animals↗
PubMed2004

CD4+ CD25+ Treg: divide and rule?

Research on CD4+ CD25+ regulatory T cells (Treg) has gathered momentum over the last five years but many aspects of their fundamental biology remain elusive. Treg have been considered to be 'naturally anergic' based on their failure to proliferate in response to T-cell receptor ligation in vitro. Several recent studies challenge this view and demonstrate a robust proliferative capacity for CD25+ cells. The significance of this finding for Treg homeostasis and function is considered below.

Animals↗
PubMed2005

Combination B7-Fc fusion protein treatment and Treg cell depletion therapy.

PURPOSE: A B7.1 fusion protein consisting of the extracellular domains of human B7.1 and the Fc portion of human IgG1, called B7.1-Fc, was generated and evaluated for its antitumor potential when used alone or in combination with regulatory T (Treg) cell depletion. METHODS: A human B7.1-Fc fusion protein was constructed, expressed, purified, and examined for its antitumor activity in experimental mouse tumor models. RESULTS: Soluble B7.1-Fc showed costimulatory activity of T-cell proliferation in vitro, and when given in vivo, it induced complete regression of Colon 26 tumors after a 5-day treatment regimen. Parallel studies with human B7.2-Fc gave very similar results in the Colon 26 tumor model. Even in mice with established RENCA and Madison 109 tumors, which are poorly immunogenic, B7.1-Fc treatment slowed tumor growth dramatically. In these models, more potent antitumor activity was achieved when B7.1-Fc was used in combination with Treg depletion by i.p. administration of antibody PC61. Rechallenge experiments done with mice that had sustained complete tumor regressions showed that these mice had immunologic memory by their ability to reject subsequent implants. Histologically, B7.1-Fc treatment induced multiple areas of necrosis and infiltration of CD4+ and CD8+ T cells in tumors along with a concomitant dramatic increase in T-cell proliferation in tumor-draining lymph nodes. CONCLUSIONS: The B7.1-Fc fusion protein seems to be an effective antitumor agent especially in combination with Treg depletion. Its potency in stimulating immune responses and its human origin suggest that clinical studies may be warranted in the future.

Animals↗
PubMed2004

CD4+ Tregs and immune control.

Recent years have seen Tregs become a popular subject of immunological research. Abundant experimental data have now confirmed that naturally occurring CD25+CD4+ Tregs in particular play a key role in the maintenance of self tolerance, with their dysfunction leading to severe or even fatal immunopathology. The sphere of influence of Tregs is now known to extend well beyond just the maintenance of immunological tolerance and to impinge on a host of clinically important areas from cancer to infectious diseases. The identification of specific molecular markers in both human and murine immune systems has enabled the unprecedented investigation of these cells and should prove key to ultimately unlocking their clinical potential.

Animals↗
PubMed2004

Tregs in T cell vaccination: exploring the regulation of regulation.

T cell vaccination (TCV) activates Tregs of 2 kinds: anti-idiotypic (anti-id) and anti-ergotypic (anti-erg). These regulators furnish a useful view of the physiology of T cell regulation of the immune response. Anti-id Tregs recognize specific effector clones by their unique TCR CDR3 peptides; anti-id networks of CD4+ and CD8+ Tregs have been described in detail. Here we shall focus on anti-erg T regulators. Anti-erg T cells, unlike anti-id T cells, do not recognize the clonal identity of effector T cells; rather, anti-erg T cells recognize the state of activation of target effector T cells, irrespective of their TCR specificity. We consider several features of anti-erg T cells: their ontogeny, subset markers, and target ergotope molecules; mechanisms by which they regulate other T cells; mechanisms by which they get regulated; and therapeutic prospects for anti-erg upregulation and downregulation.

Animals↗
PubMed2006

Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs.

IFN-gamma is an important Th1 proinflammatory cytokine and has a paradoxical effect on EAE in which disease susceptibility is unexpectedly heightened in IFN-gamma-deficient mice. In this study, we provide what we believe is new evidence indicating that IFN-gamma is critically required for the conversion of CD4+ CD25- T cells to CD4+ Tregs during EAE. In our study, the added severity of EAE in IFN-gamma knockout mice was directly associated with altered encephalitogenic T cell responses, which correlated with reduced frequency and function of CD4+ CD25+ Foxp3+ Tregs when compared with those of WT mice. It was demonstrated in both human and mouse systems that in vitro IFN-gamma treatment of CD4+ CD25- T cells led to conversion of CD4+ Tregs as characterized by increased expression of Foxp3 and enhanced regulatory function. Mouse CD4+ CD25- T cells, when treated in vitro with IFN-gamma, acquired marked regulatory properties as evidenced by suppression of EAE by adoptive transfer. These findings have important implications for the understanding of the complex role of IFN-gamma in both induction and self regulation of inflammatory processes.

Amino Acid Sequence↗