Subject(s)
Mutation , T-Lymphocytes , Humans , T-Lymphocytes/immunology , Cell- and Tissue-Based TherapyABSTRACT
In autoimmunity, FOXP3+ Tregs skew toward a proinflammatory, nonsuppressive phenotype and are, therefore, unable to control the exaggerated autoimmune response. This largely affects the success of autologous Treg therapy, which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the CNS during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss of function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential and a proinflammatory Th1/17 signature, and they upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less-suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In summary, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive proinflammatory phenotype switch. These insights help improve the efficacy of autologous Treg therapy of MS.
Subject(s)
Autoimmune Diseases , Multiple Sclerosis , Humans , Mice , Animals , Sirolimus/pharmacology , Blood-Brain Barrier/metabolism , T-Lymphocytes, Regulatory , Endothelial Cells/metabolism , Cytokines/metabolism , Multiple Sclerosis/drug therapy , Mechanistic Target of Rapamycin Complex 1/metabolismABSTRACT
Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.
Subject(s)
Neoplasms , Proteogenomics , Humans , Neoplasms/genetics , Antigens, Neoplasm/genetics , PeptidesABSTRACT
Adoptive cell therapy (ACT) has seen a steep rise of new therapeutic approaches in its immune-oncology pipeline over the last years. This is in great part due to the recent approvals of chimeric antigen receptor (CAR)-T cell therapies and their remarkable efficacy in certain soluble tumors. A big focus of ACT lies on T cells and how to genetically modify them to target and kill tumor cells. Genetically modified T cells that are currently utilized are either equipped with an engineered CAR or a T cell receptor (TCR) for this purpose. Both strategies have their advantages and limitations. While CAR-T cell therapies are already used in the clinic, these therapies face challenges when it comes to the treatment of solid tumors. New designs of next-generation CAR-T cells might be able to overcome these hurdles. Moreover, CARs are restricted to surface antigens. Genetically engineered TCR-T cells targeting intracellular antigens might provide necessary qualities for the treatment of solid tumors. In this review, we will summarize the major advancements of the CAR-T and TCR-T cell technology. Moreover, we will cover ongoing clinical trials, discuss current challenges, and provide an assessment of future directions within the field.
Subject(s)
Neoplasms , Receptors, Chimeric Antigen , Humans , Receptors, Antigen, T-Cell , Neoplasms/genetics , Neoplasms/therapy , Immunotherapy, Adoptive , T-LymphocytesABSTRACT
Background: Optical coherence tomography angiography (OCT-A) is a novel technique allowing non-invasive assessment of the retinal vasculature. During relapsing remitting multiple sclerosis (RRMS), retinal vessel loss occurs in eyes suffering from acute optic neuritis and recent data suggest that retinal vessel loss might also be evident in non-affected eyes. We investigated whether alterations of the retinal vasculature are linked to the intrathecal immunity and whether they allow prognostication of the future disease course. Material and methods: This study includes two different patient cohorts recruited at a tertiary German academic multiple sclerosis center between 2018 and 2020 and a cohort of 40 healthy controls. A total of 90 patients with RRMS undergoing lumbar puncture and OCT-A analysis were enrolled into a cross-sectional cohort study to search for associations between the retinal vasculature and the intrathecal immune compartment. We recruited another 86 RRMS patients into a prospective observational cohort study who underwent clinical examination, OCT-A and cerebral magnetic resonance imaging at baseline and during annual follow-up visits to clarify whether alterations of the retinal vessels are linked to RRMS disease activity. Eyes with a history of optic neuritis were excluded from the analysis. Results: Rarefication of the superficial vascular complex occured during RRMS and was linked to higher frequencies of activated B cells and higher levels of the pro-inflammatory cytokines interferon-γ, tumor necrosis factor α and interleukin-17 in the cerebrospinal fluid. During a median follow-up of 23 (interquartile range 14 - 25) months, vessel loss within the superficial (hazard ratio [HR] 1.6 for a 1%-point decrease in vessel density, p=0.01) and deep vascular complex (HR 1.6 for a 1%-point decrease, p=0.05) was associated with future disability worsening. Discussion: Optic neuritis independent rarefication of the retinal vasculature might be linked to neuroinflammatory processes during RRMS and might predict a worse disease course. Thus, OCT-A might be a novel biomarker to monitor disease activity and predict future disability.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Optic Neuritis , Humans , Multiple Sclerosis/pathology , Cross-Sectional Studies , Prospective Studies , Retinal Vessels/diagnostic imaging , Retinal Vessels/pathology , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/pathology , Disease ProgressionABSTRACT
IL-6 gained much attention with the discovery that this cytokine is a non-redundant differentiation factor for Th17 cells and T follicular helper cells. Adaptive immune responses to fungi and extracellular bacteria are impaired in the absence of IL-6. IL-6 is also required for the induction of ROR-γt+ Treg cells, which are gatekeepers of homeostasis in the gut lamina propria in the presence of commensal bacteria. Conversely, severe immunopathology in T cell-mediated autoimmunity is mediated by Th17 cells that rely on IL-6 for their generation and maintenance. Recently, it has been discovered that the differentiation of these distinct T helper cell subsets may be linked to distinct signaling modalities of IL-6. Here, we summarize the current knowledge on the mode of action of IL-6 in the differentiation and maintenance of T cell subsets and propose that a context-dependent understanding of the impact of IL-6 on T cell subsets might inform rational IL-6-directed interventions in autoimmunity and chronic inflammation.
Subject(s)
Cell Lineage , Interleukin-6/metabolism , T-Lymphocyte Subsets/cytology , Animals , Autoimmunity , Humans , Signal TransductionABSTRACT
Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
Subject(s)
Autoimmunity , Brain/immunology , Cell Lineage , Encephalomyelitis, Autoimmune, Experimental/immunology , Intestines/immunology , Skin/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adoptive Transfer , Animals , Autoimmunity/drug effects , Brain/drug effects , Brain/metabolism , Calcium Signaling , Cerebrospinal Fluid/immunology , Cerebrospinal Fluid/metabolism , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Fingolimod Hydrochloride/pharmacology , Gene Expression Profiling , Genes, T-Cell Receptor , HEK293 Cells , Humans , Immunosuppressive Agents/pharmacology , Intestines/drug effects , Intravital Microscopy , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/metabolism , Phenotype , Prospective Studies , RNA-Seq , Receptors, CXCR6/genetics , Receptors, CXCR6/metabolism , Receptors, Purinergic P2X7/genetics , Receptors, Purinergic P2X7/metabolism , Single-Cell Analysis , Skin/drug effects , Skin/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/transplantation , TranscriptomeABSTRACT
Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Melanoma/immunology , Myeloid-Derived Suppressor Cells/immunology , Pyruvaldehyde/metabolism , Amine Oxidase (Copper-Containing)/metabolism , Animals , CD8-Positive T-Lymphocytes/transplantation , Cell Communication , Cell Proliferation , Humans , Immune Tolerance , Lymphocyte Activation , Melanoma, Experimental , Mice , Mice, Transgenic , Neoplasms, Experimental , Programmed Cell Death 1 Receptor/metabolismABSTRACT
Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
Subject(s)
DNA Methylation , Encephalomyelitis, Autoimmune, Experimental/immunology , Forkhead Transcription Factors/genetics , Positive Regulatory Domain I-Binding Factor 1/genetics , Positive Regulatory Domain I-Binding Factor 1/immunology , T-Lymphocytes, Regulatory/immunology , Animals , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/immunology , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Epigenesis, Genetic , Female , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/immunology , Genomic Imprinting , Interleukin-6/immunology , Male , Mice , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/metabolismABSTRACT
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS.
Subject(s)
Autoimmunity/immunology , B-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Multiple Sclerosis/immunology , Myeloid-Derived Suppressor Cells/immunology , Adolescent , Adult , Animals , Central Nervous System/immunology , Female , Humans , Male , Mice , Middle Aged , Young AdultABSTRACT
T helper (Th)17 cells are responsible for host defense against fungi and certain extracellular bacteria but have also been reported to play a role in a variety of autoimmune diseases. Th17 cells respond to environmental cues, are very plastic, and might also be involved in tissue homeostasis and regeneration. The imprinting of pathogenic properties in Th17 cells in autoimmunity seems highly dependent on interleukin (IL)-23. Since Th17 cells were first described in experimental autoimmune encephalomyelitis, they have been suggested to also promote tissue damage in multiple sclerosis (MS). Indeed, some studies linked Th17 cells to disease severity in MS, and the efficacy of anti-IL-17A therapy in MS supported this idea. In this review, we will summarize molecular features of Th17 cells and discuss the evidence for their function in experimental models of autoimmune diseases and MS.