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Succinate is a Krebs cycle intermediate. Carballido and colleagues show that succinate released by necrotic cells also functions as an 'alarmin' by activating dendritic cells that express the succinate receptor GPR91. Succinate acts as an extracellular mediator signaling through the G protein–coupled receptor GPR91. Here we show that dendritic cells had high expression of GPR91. In these cells, succinate triggered intracellular calcium mobilization, induced migratory responses and acted in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines. Succinate also enhanced antigen-specific activation of human and mouse helper T cells. GPR91-deficient mice had less migration of Langerhans cells to draining lymph nodes and impaired tetanus toxoid–specific recall T cell responses. Furthermore, GPR91-deficient allografts elicited weaker transplant rejection than did the corresponding grafts from wild-type mice. Our results suggest that the succinate receptor GPR91 is involved in sensing immunological danger, which establishes a link between immunity and a metabolite of cellular respiration.

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.

Psoriatic skin lesions are characterized by an inflammatory infiltrate, consisting of dendritic cells, monocytes, and both CD4+ and CD8+ T lymphocytes. Although the chemokines involved in the migration of CD4+ T cells into psoriatic skin are well characterized, those regulating CD8+ T-cell recruitment are less understood. We found that the percentages of peripheral blood CD8+ T cells expressing CXCR6 were higher in psoriatic patients than in healthy or atopic individuals. In addition, CXCR6 expression in psoriatic patients was more abundant in the CD8+ than in the CD4+ T-cell compartment. CXCR6 mRNA expression was also stronger in skin CD8+ T cells than in the corresponding blood-derived counterparts. Immunofluorescence analysis revealed profound upregulation of the CXCR6 ligand CXCL16 by monocytes, keratinocytes, and dendritic cells in psoriatic skin compared with healthy or atopic dermatitis skin. In line with this, CXCR6+ CD8+ T cells also were most prevalent in psoriatic skin. Furthermore, CXCL16 induced Ca2+ influx and chemotactic migration of psoriatic skin-derived CD8+ T cells in vitro. Most importantly, CXCL16 potently recruited human CD8+ T cells to human skin grafts previously transplanted onto SCID mice in vivo. These investigations indicate that CXCL16–CXCR6 interactions mediate homing of CD8+ T cells into human skin, and thereby contribute to psoriasis pathogenesis.

Characterizing antigen-specific T cell responses is essential for understanding the immunogenicity of biotherapeutics and mitigating drug-specific immune reactions. This study describes a flow cytometry composite Activation-Induced Marker (cAIM) assay for cynomolgus monkeys that allows quantification of T cell recall responses to multiple antigens using up to ten AIM pairs. The procedure incorporates two composite metrics (cAIM-index and cAIM-score) that facilitate the summation of T cell recall responses into interpretable numeric values, reducing reliance on multiple graphical comparisons. The assay is compatible with human and mouse samples and can utilize peripheral blood mononuclear cells or whole blood. Additionally, the method is well suited for the mass cytometry platform, enabling the detection of antigen-specific CD4 and CD8 T cell recall responses while providing deep immunophenotype information and consuming minimal blood sample volumes. The assay successfully enables quantification of antigen-specific T cell recall responses across multiple antigens and species, while composite metrics streamline interpretation. These protocols shall support preclinical and clinical immunogenicity assessments, advancing biotherapeutic development.

Antigen-specific immunotherapy (ASI) holds great promise for type 1 diabetes (T1D). Preclinical success for this approach has been demonstrated in vivo , however, clinical translation is still pending. Reasons explaining the slow progress to approve ASI are complex and span all stages of research and development, in both academic and industry environments. The basic four hurdles comprise a lack of translatability of pre-clinical research to human trials; an absence of robust prognostic and predictive biomarkers for therapeutic outcome; a need for a clear regulatory path addressing ASI modalities; and the limited acceptance to develop therapies intervening at the pre-symptomatic stages of disease. The core theme to address these challenges is collaboration—early, transparent, and engaged interactions between academic labs, pharmaceutical research and clinical development teams, advocacy groups, and regulatory agencies to drive a fundamental shift in how we think and treat T1D.

Ofatumumab is the first, fully human, anti-CD20 monoclonal antibody in Phase 3 development for multiple sclerosis (MS). The study focused on changes in lymphocyte subsets in blood and lymphoid tissues and on potential novel biomarkers as a result of anti-CD20 antibody action in Cynomolgus monkeys treated with human equivalent doses of subcutaneous (s.c.) ofatumumab on Days 0, 7, and 14. Axillary lymph nodes (LNs) and blood samples were collected at various time points until Day 90. Lymphocyte subsets were quantified by flow cytometry, while morphological and immune cell changes were assessed by imaging mass cytometry (IMC), immunohistochemistry (IHC), in situ hybridization (ISH), and transcriptome analyses using single-cell methodology. Ofatumumab treatment resulted in a potent and rapid reduction of B cells along with a simultaneous drop in CD20 T cell counts. At Day 21, IHC revealed B-cell depletion in the perifollicular and interfollicular area of axillary LNs, while only the core of the germinal center was depleted of CD20 CD21 cells. By Day 62, the perifollicular and interfollicular areas were abundantly infiltrated by CD21 B cells and this distribution returned to the baseline cytoarchitecture by Day 90. By IMC CD20 CD3 CD8 cells could be identified at the margin of the follicles, with a similar pattern of distribution at Day 21 and 90. Single-cell transcriptomics analysis showed that ofatumumab induced reversible changes in t-distributed stochastic neighbor embedding (t-SNE) defined B-cell subsets that may serve as biomarkers for drug action. In summary, low dose s.c. ofatumumab potently depletes both B cells and CD20 T cells but apparently spares marginal zone (MZ) B cells in the spleen and LN. These findings add to our molecular and tissue-architectural understanding of ofatumumab treatment effects on B-cell subsets.

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T‐cell activation and fate after engagement of the T‐cell receptor pathway. We show that MLT‐827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T‐cell activation, in contrast to the pan‐protein kinase C inhibitor AEB071. However, MLT‐827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL‐2 production as well as reduced expression of the IL‐2 receptor alpha subunit (CD25), resulting from defective canonical NF‐κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT‐827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T‐cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion. MLT‐827 is the first potent and selective Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) paracaspase inhibitor. It does not block the initial phase of T‐cell activation. However, work with MLT‐827 elucidates how MALT1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion.

Background Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models. Results We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases. Conclusions These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy.

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes. Orally delivered nanocarriers of insulin or rapamycin made from a polymeric bile acid exert metabolic and immunomodulatory functions, restore blood-glucose levels in mice and pigs with type 1 diabetes, and delay the onset of diabetes in mice.

Since the first description of the subpopulations of TH1 and TH2 cells, insights into the development and control of these cells as two polarized and physiologically balanced subsets have been generated. In particular, implications of the TH1-TH2 concept for TH cell–mediated skin disorders have been discovered. This article will review the basic factors that control the development of TH1 and TH2 cells, such as the cytokines IL-12 and IL-4 and transcription factors, the possible role of costimulatory molecules, and specialized dendritic cell populations. These regulatory mechanisms will be discussed in the context of polarized TH1 or TH2 skin disorders such as psoriasis and atopic dermatitis. Also presented are the principles that govern how chemokines and chemokine receptors recruit TH1 and TH2 cells to inflammatory sites and how they amplify these polarized TH cell responses. All of these concepts, including a novel role for IL-4–inducing TH1 responses, can contribute to the design of better therapeutic strategies to modulate TH cell–mediated immune responses.