Polyclonally Derived Alloantigen-Specific T Regulatory Cells Exhibit Target-Specific Suppression and Capture MHC Class II from Dendritic Cells.

Foxp3+ T regulatory (Treg) cells prevent allograft rejection and graft-versus-host disease. Although polyclonal Tregs have been used both in animal models and in humans, the fine specificity of their suppressive function is poorly defined. We have generated mouse recipient-derived alloantigen-specific Tregs in vitro and explored the fine specificity of their suppressive function and their mechanism of action in vitro and in vivo.

Illuminating T cell-dendritic cell interactions in vivo by FlAsHing antigens.

Delineating the complex network of interactions between antigen-specific T cells and antigen presenting cells (APCs) is crucial for effective precision therapies against cancer, chronic infections, and autoimmunity. However, the existing arsenal for examining antigen-specific T cell interactions is restricted to a select few antigen-T cell receptor pairs, with limited in situ utility. This lack of versatility is largely due to the disruptive effects of reagents on the immune synapse, which hinder real-time monitoring of antigen-specific interactions.

Disabled C3ar1/C5ar1 Signaling in Foxp3+ T Regulatory Cells Leads to TSDR Demethylation and Long-Term Stability.

Demethylation of the T regulatory cell (Treg)-specific demethylation region (TSDR) of the Foxp3 gene is the hallmark of Foxp3+ Treg stability, but the cellular signaling that programs this epigenetic state remains undefined. In this article, we show that suppressed C3a and C5a receptor (C3ar1/C5ar1) signaling in murine Tregs plays an obligate role. Murine C3ar1-/-C5ar1-/- Foxp3+ cells showed increased suppressor of cytokine signaling 1/2/3 expression, vitamin C stabilization, and ten-eleven translocation (TET) 1, TET2, and TET3 expression, all of which are linked to Treg stability.

Illuminating T cell-dendritic cell interactions in vivo by FlAsHing antigens.

Delineating the complex network of interactions between antigen-specific T cells and antigen presenting cells (APCs) is crucial for effective precision therapies against cancer, chronic infections, and autoimmunity. However, the existing arsenal for examining antigen-specific T cell interactions is restricted to a select few antigen-T cell receptor pairs, with limited in situ utility. This lack of versatility is largely due to the disruptive effects of reagents on the immune synapse, which hinder real-time monitoring of antigen-specific interactions.

Co-expression of Foxp3 and Helios facilitates the identification of human T regulatory cells in health and disease.

Foxp3 is regarded as the major transcription factor for T regulatory (T) 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) cells activated by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a T marker in man.

Control of Memory Phenotype T Lymphocyte Homeostasis: Role of Costimulation.

Foxp3 T regulatory cells (Tregs), CD4Foxp3 T cells, and CD8 T cells are composed of naive phenotype (NP) and memory phenotype (MP) subsets. Ten to 20% of each MP T cell population are cycling (Ki-67) in vivo. We investigated the contribution of costimulatory (CD28) and coinhibitory (CTLA-4, PD-1) receptors on MP T cell homeostatic proliferation in vivo in the mouse.

IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms.

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.

Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells.

Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage.

Control of regulatory T cell homeostasis.

CD4 Foxp3 T Regulatory (Treg) cells play a critical role in the homeostasis and maintenance of the immune system. The understanding of different aspects of Treg cells biology remains an intensively investigated subject as altering their generation, stability, or function by drugs or biologics may have therapeutic value in the treatment of autoimmune and inflammatory diseases as well as cancers. This review will focus on recent studies on the role of cytokines, T Cell Receptor (TCR) and co-stimulatory/co-inhibitory molecules signaling, location and metabolism on the homeostasis and stability of Treg cells.

Regulatory T cells: Master thieves of the immune system.

Treg cells are the immune system's in-house combatants against pathological immune activation. Because they are vital to maintenance of peripheral tolerance, it is important to understand how they perform their functions. To this end, various mechanisms have been proposed for Treg-mediated immune inhibition.

Type I IFN signaling in T regulatory cells modulates chemokine production and myeloid derived suppressor cells trafficking during EAE.

Interferon-β has therapeutic efficacy in Multiple Sclerosis by reducing disease exacerbations and delaying relapses. Previous studies have suggested that the effects of type I IFN in Experimental Autoimmune Encephalomyelitis (EAE) in mice were targeted to myeloid cells. We used mice with a conditional deletion (cKO) of the type I IFN receptor (IFNAR) in T regulatory (Treg) cells to dissect the role of IFN signaling on Tregs.

Cutting Edge: Inhibition of the Interaction of NK Inhibitory Receptors with MHC Class I Augments Antiviral and Antitumor Immunity.

NK cells recognize MHC class I (MHC-I) Ags via stochastically expressed MHC-I-specific inhibitory receptors that prevent NK cell activation via cytoplasmic ITIM. We have identified a pan anti-MHC-I mAb that blocks NK cell inhibitory receptor binding at a site distinct from the TCR binding site. Treatment of unmanipulated mice with this mAb disrupted immune homeostasis, markedly activated NK and memory phenotype T cells, enhanced immune responses against transplanted tumors, and augmented responses to acute and chronic viral infection.

T Follicular Regulatory Cell Suppression of T Follicular Helper Cell Function Is Context-Dependent .

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.

Salt Sensing by Serum/Glucocorticoid-Regulated Kinase 1 Promotes Th17-like Inflammatory Adaptation of Foxp3 Regulatory T Cells.

Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells.

Helios: still behind the clouds.

Regulatory T (Treg) cells are a subset of CD4 T cells that are critical for the maintenance of self-tolerance. The forkhead box transcription factor Foxp3 is a master regulator for the Treg phenotype and function and its expression is essential in Treg cells, as the loss of Foxp3 results in lethal autoimmunity. Two major subsets of Treg cells have been described in vivo; thymus-derived Treg (tTreg) cells that develop in the thymus and peripherally induced Treg (pTreg) cells that are derived from conventional CD4  Foxp3 T cells and are converted in peripheral tissues to cells that express Foxp3 and acquire suppressive ability.

Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity.

Eos (lkzf4) is a member of the Ikaros family of transcription factors and is preferentially expressed in T-regulatory (Treg) cells. However, the role of Eos in Treg function is controversial. One study using siRNA knock down of Eos demonstrated that it was critical for Treg suppressor function.

Helios Deficiency Predisposes the Differentiation of CD4Foxp3 T Cells into Peripherally Derived Regulatory T Cells.

The transcription factor Helios is expressed in a large percentage of Foxp3 regulatory T (Treg) cells and is required for the maintenance of their suppressive phenotype, as mice with a selective deficiency of Helios in Treg cells spontaneously develop autoimmunity. However, mice with a deficiency of Helios in all T cells do not exhibit autoimmunity, despite the defect in the suppressor function of their Treg cell population, suggesting that Helios also functions in non-Treg cells. Although Helios is expressed in a small subset of CD4Foxp3 and CD8 T cells and its expression is upregulated upon T cell activation, its function in non-Treg cells remains unknown.

Unmet need in rheumatology: reports from the Targeted Therapies meeting 2018.

To develop a comprehensive listing of the greatest unmet scientific and clinical needs in rheumatology. The 20th annual international Targeted Therapies meeting brought more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of five disease-specific groups with 20-30 experts assigned to each group based on expertise.

CD47 Expression in Natural Killer Cells Regulates Homeostasis and Modulates Immune Response to Lymphocytic Choriomeningitis Virus.

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.

Regulatory T cells mediate specific suppression by depleting peptide-MHC class II from dendritic cells.

Regulatory T cells (T cells) can activate multiple suppressive mechanisms in vitro after activation via the T cell antigen receptor, resulting in antigen-independent suppression. However, it remains unclear whether similar pathways operate in vivo. Here we found that antigen-specific T cells activated by dendritic cells (DCs) pulsed with two antigens suppressed conventional naive T cells (T cells) specific for both cognate antigens and non-cognate antigens in vitro but suppressed only T cells specific for cognate antigen in vivo.

Helios and Helios Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.

The transcription factor Helios is expressed in a large subset of Foxp3 Tregs. We previously proposed that Helios is a marker of thymic derived Treg (tTreg), while Helios Treg were induced from Foxp3 T conventional (Tconv) cells in the periphery (pTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice.

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia.

SAMHD1 Posttranscriptionally Controls the Expression of Foxp3 and Helios in Human T Regulatory Cells.

Clinical application of Ag-specific T regulatory cells (Tregs) offers promise for the treatment of undesirable immune diseases. To achieve this goal, long-term expansion of Tregs is required to obtain sufficient numbers of cells. However, human Tregs are not stable ex vivo.

PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells.

CD4 T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3 Th1 cells (denoted as TbetiTreg cells) and inducible regulatory T (iTreg) cells. TbetiTreg cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD).