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T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3. In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic. The major issue that remains to be resolved is how they mediate their suppressive functions. In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms. Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites. Many of the concepts we have developed are based on studies, and it remains unclear if these concepts can readily be applied to Treg function . Our lack of a specific cell surface marker that readily allows us to identify and target Treg , particularly in man, remains a major stumbling block. Finally, I will review in some detail controversies regarding the origin of Treg, thymus versus periphery, and attempts to reverse Treg suppression by targeting antigens on their cell surface, particularly members of the TNF receptor superfamily. Hopefully, these areas of controversy will be resolved by in depth studies over the next few years and manipulation of Treg function will be placed on a more solid experimental footing.

Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models. In both viral infection and tumor models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced Treg associated activation antigens. LCMV-specific CD8+ T cells and tumor infiltrating lymphocytes from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral and antitumor IFN-γ and TNF-α. In chronic viral model, the numbers of antiviral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs during chronic infection, and higher tumor burden than the WT controls. The enhanced activated phenotype was evident through transcriptome analysis of IFNARfl/flxFoxp3YFP-Cre mice Tregs during infection demonstrated differential expression of a unique gene signature characterized by elevated levels of genes involved in suppression and decreased levels of genes mediating apoptosis. Thus, IFN signaling in Tregs is beneficial to host resulting in a more effective antiviral response and augmented antitumor immunity.

TGF-β family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-β is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFβ-binding protein (LTBP) to produce a large latent form. Latent TGF-β is also found on the surface of activated FOXP3⁺ regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-β to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-β and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-β expression on activated Tregs and recombinant latent TGF-β1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-β on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism.

How GITR (glucocorticoid-induced tumour-necrosis-factor-receptor-related protein) regulates an immune response is not clearly understood. This article proposes a model in which the interaction of GITR with its ligand co-stimulates the respective functions of both responder T cells and CD4 + CD25 + regulatory T cells. Stimulation of T cells through GITR (glucocorticoid-induced tumour-necrosis-factor-receptor-related protein) has been shown to enhance immunity to tumours and viral pathogens, and to exacerbate autoimmune disease. The effects of stimulation through GITR are generally thought to be caused by attenuation of the effector activity of immunosuppressive CD4 + CD25 + regulatory T (T Reg ) cells. Here we propose a model in which GITR–GITR-ligand interactions co-stimulate both responder T-cell functions and the suppressive functions of T Reg cells.

Foxp3 is regarded as the major transcription factor for T regulatory (T reg ) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4 + T conventional (T conv ) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a T reg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3 + T reg cells and can potentially serve as a marker of human T reg . Here, we confirm that Foxp3 expression is readily upregulated by T conv upon TCR stimulation in vitro , while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hT conv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4 + T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon T conv cell activation in vivo and that Foxp3 expression alone can be used to quantitate T reg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of T reg in humans.

CD47 is a ubiquitous cell surface receptor that directly regulates T cell immunity by interacting with its inhibitory ligand thrombospondin-1 and limits clearance of cells by phagocytes that express its counter-receptor signal-regulatory protein-α. Murine natural killer (NK) cells express higher levels of CD47 than other lymphocytes, but the role of CD47 in regulating NK cell homeostasis and immune function remains unclear. mice exhibited depletion of NK precursors in bone marrow, consistent with the antiphagocytic function of CD47. In contrast, antisense CD47 knockdown or gene disruption resulted in a dose dependent accumulation of immature and mature NK cells in spleen. Mature NK cells exhibited increased expression of NK effector and interferon gene signatures and an increased proliferative response to interleukin-15 . mice showed no defect in their early response to acute Armstrong lymphocytic choriomeningitis virus (LCMV) infection but were moderately impaired in controlling chronic Clone-13 LCMV infection, which was associated with depletion of splenic NK cells and loss of effector cytokine and interferon response gene expression in NK cells. Broad CD47-dependent differences in NK activation, survival, and exhaustion pathways were observed in NK cell transcriptional signatures in LCMV infected mice. These data identify CD47 as a cell-intrinsic and systemic regulator of NK cell homeostasis and NK cell function in responding to a viral infection.

Glycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish. To evaluate the role of GARP in platelet physiology and in thrombus formation using platelet and endothelial conditional GARP knock out mice. Platelet and endothelial specific GARP knockout mice were generated using the Cre-loxP recombination system. The function of platelets without GARP was measured by flow cytometry, spreading analysis and aggregometry using PAR4-activating peptide and collagen related peptide. Additionally, clot retraction and collagen-induced platelet adhesion and aggregation under flow were analyzed. Finally, in vivo tail bleeding time, occlusion time of the mesenteric and carotid artery after FeCl3-induced thrombosis were determined in platelet and endothelial specific GARP knock out mice. Platelet specific GARP knockout mice had normal surface GPIb, GPVI and integrin αIIb glycoprotein expression. Although GARP expression was increased upon platelet activation, platelets without GARP displayed normal agonist induced activation, spreading on fibrinogen and aggregation responses. Furthermore, absence of GARP on platelets did not influence clot retraction and had no impact on thrombus formation on collagen-coated surfaces under flow. In line with this, neither the tail bleeding time nor the occlusion time in the carotid- and mesenteric artery after FeCl3-induced thrombus formation in platelet or endothelial specific GARP knock out mice were affected. Evidence is provided that platelet and endothelial GARP are not important in hemostasis and thrombosis in mice.

The production of antibody-secreting plasma cells and memory B cells requires the interaction of T follicular helper (Tfh) cells with B cells in the follicle and is modulated by T follicular regulatory (Tfr) cells. We compare the effects of Tfr cells in an model of bystander Tfh function in the absence of BCR engagement and in a model in which mimics cognate T-B interactions in which the BCR is engaged. In the absence of Tfr cells, Tfh cells from primed mice induce naive B cell differentiation into GC B cells and class switch recombination (CSR) in the presence of anti-CD3 alone or anti-CD3/IgM in a contact-dependent manner. Addition of primed Tfr cells efficiently suppressed GC B cell proliferation, differentiation and CSR in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. When stimulated with anti-CD3 alone, IL-4 is critical for the induction of GC B cells and CSR. IL-21 plays a minimal role in GC B cell differentiation, but a greater role in switching. When the BCR is engaged, IL-4 is primarily required for switching and IL-21 only modestly affects switching. CD40L expression was critical for Tfh-mediated B cell proliferation/differentiation in the absence of B cell engagement. When the BCR was engaged, proliferation of CD40 deficient B cells was partially restored, but was susceptible to suppression by Tfr. These studies suggest that Tfr suppressor function is complex and is modulated by BCR signaling and CD40-CD40L interactions.

Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE-/- mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35-deficient (IL-35P35-deficient) mice on an ApoE-/- background and found Treg reduction in the spleen and aorta compared with ApoE-/- controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE-/- Tregs, and we have validated higher CCR5 expression in ApoE-/- Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE-/- have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.

The authors of some of our most popular Reviews look back on a decade of immunology. As Nature Reviews Immunology reaches its 10 th anniversary, the authors of one of the top-cited articles from each year take a trip down memory lane. We've asked them to look back on the state of research at the time their Review was published, to consider why the article has had the impact it has and to discuss the future directions of their field. This Viewpoint article provides an interesting snapshot of some of the fundamental advances in immunology over the past 10 years. Highlights include our improved understanding of Toll-like receptor signalling, and of immune regulation mediated by regulatory T cells, indoleamine 2,3-dioxygenase, myeloid-derived suppressor cells and interleukin-10. The complexities in the development and heterogeneity of macrophages, dendritic cells and T helper cells continue to engage immunologists, as do the immune processes involved in diseases such as atherosclerosis. We look forward to what the next 10 years of immunology research may bring.