Relationship Between T-Cell Exosomes and Cellular Subsets in SLE According to Type I IFN-Signaling

Objective: To quantify the levels of circulating exosomes derived from T-cells and monocytes and their possible associations with leukocyte subpopulations and cytokine milieu in Systemic Lupus Erythematosus (SLE).Methods: Total circulating exosomes (CD9+-Ex) and those derived from T-cells (CD3+-Ex) and monocytes (CD14+-Ex) were quantified by flow cytometry in 82 SLE patients and 32 controls. Leukocyte subsets and serum cytokines were analyzed by flow cytometry or by immunoassays. IFN-score was evaluated by real time RT-PCR in whole blood samples from a subgroup of 73 patients and 24 controls.Results: Activation markers (IFNR1 and BLyS) on monocytes, neutrophils and B-cells correlated inversely with circulating exosomes (CD9+-Ex, CD3+-Ex, and CD14+-Ex) in controls but directly with CD3+-Ex in patients (all p < 0.05). Although CD9+-Ex were increased in SLE, no differences were found in CD3+-Ex, supporting that exosome content accounts for this opposite role. Interestingly, CD4+CD28null cells correlated with CD3+-Ex in patients and controls, and displayed similar associations with leukocyte subsets in both groups. Additionally, CD3+-Ex correlated in patients with the expression of CD25 in CD4+CD28null cells. Furthermore, the activated status of this senescent subset was related to IFNα serum levels in controls and to IFN-score in SLE patients. Finally, patients presenting high IFN-score, in addition to elevated CD25+CD28null cells associated with the activation of myeloid cells, displayed higher levels of inflammatory cytokines and chemokines.Conclusion: Our results support a relationship between T-cell exosomes and cellular subsets in SLE according to type I IFN-signaling, which could amplify chronic immune activation and excessive cytokine/chemokine response.

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

Nature Communications ◽

10.1038/s41467-021-22312-y ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Norzawani Buang ◽

Lunnathaya Tapeng ◽

Victor Gray ◽

Alessandro Sardini ◽

Chad Whilding ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208055 ◽

2015 ◽

Vol 75 (9) ◽

pp. 1728-1734 ◽

Cited By ~ 23

Author(s):

Dag Leonard ◽

Maija-Leena Eloranta ◽

Niklas Hagberg ◽

Olof Berggren ◽

Karolina Tandre ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Complexes ◽

Serum Levels ◽

Plasmacytoid Dendritic Cells ◽

Interferon Α ◽

Type I ◽

Activated T Cells ◽

Gm Csf

ObjectivesPatients with systemic lupus erythematosus (SLE) have an ongoing interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs). We investigated whether T cells can promote IFN-α production by pDCs.MethodsHuman pDCs were stimulated with immune complexes (ICs) containing U1 small nuclear ribonucleic proteins particles and SLE-IgG (RNA-IC) in the presence of T cells or T cell supernatants. T cells were activated by anti-CD3/CD28 antibodies or in a mixed leucocyte reaction. IFN-α and other cytokines were determined in culture supernatants or patient sera with immunoassays. The effect of interleukin (IL) 3 and granulocyte-macrophage-colony-stimulating factor (GM-CSF) on pDCs was examined by the use of antibodies, and the expression of CD80/CD86 was determined using flow cytometry.ResultsActivated T cells and supernatants from activated T cells increased IFN-α production by >20-fold. The stimulatory effect of T cell supernatants was reduced after depletion of GM-CSF (81%) or by blocking the GM-CSF receptor (55%–81%). Supernatant from activated T cells, furthermore, increased the frequency of CD80 and CD86 expressing pDCs stimulated with RNA-IC from 6% to 35% (p<0.05) and from 10% to 26% (p<0.01), respectively. Activated SLE T cells enhanced IFN-α production to the same extent as T cells from healthy individuals and a subset of patients with SLE had increased serum levels of GM-CSF.ConclusionsActivated T cells enhance IFN-α production by RNA-IC stimulated pDCs via GM-CSF and induce pDC maturation. Given the increased serum levels of GM-CSF in a subset of patients with SLE, these findings suggest that activated T cells may upregulate type I IFN production in SLE.

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Neutrophil and lymphocyte counts are associated with different immunopathological mechanisms in systemic lupus erythematosus

Lupus Science & Medicine ◽

10.1136/lupus-2020-000382 ◽

2020 ◽

Vol 7 (1) ◽

pp. e000382

Author(s):

Bobby Kwanghoon Han ◽

Katherine D Wysham ◽

Kevin C Cain ◽

Helena Tyden ◽

Anders A Bengtsson ◽

...

Keyword(s):

Neutrophil Count ◽

Lupus Erythematosus ◽

Lymphocyte Count ◽

Neutrophil Activation ◽

Type I ◽

Healthy Controls ◽

Type I Ifn ◽

Healthy Individuals ◽

Activation Markers ◽

The Individual

ObjectiveNeutrophils contribute to the SLE pathogenesis. Neutrophil to lymphocyte ratio (NLR) is reported to correlate with disease activity in SLE. The aim of the study was to evaluate whether NLR reflects underlying immunopathogenic activity in SLE, as well as to determine the contribution of each component of NLR, neutrophil and lymphocyte count.MethodsData were obtained from a cohort of patients with SLE (n=141) recruited at Lund University, Sweden. NLR levels were compared between patients with SLE and healthy controls (n=79). The relationship between NLR and clinical and immunological markers was examined using Mann-Whitney U test and logistic regression analysis. High NLR was defined as above the 90th percentile of healthy individuals.ResultsPatients with SLE had elevated neutrophil count (p=0.04) and reduced lymphocyte count (p<0.0001), resulting in elevated NLR as compared with healthy controls (p<0.0001). Patients with high NLR had more active disease, and were more frequently on prednisone use and immunosuppressive medicines. High NLR was associated with immune complex (IC)-driven disease with presence of antidouble-stranded DNA antibodies (p=0.006), circulating ICs (p=0.02) and type I interferon (IFN) activity (p=0.009). Further, high NLR was associated with neutrophil abnormalities, including enrichment for low-density granulocytes (LDGs) (p=0.001), and increased levels of the serum neutrophil activation marker, calprotectin (p=0.02). Assessing the individual components within NLR, that is, neutrophil and lymphocyte count, high neutrophil count was associated with neutrophil activation markers (p<0.0001), whereas low lymphocyte count was associated with type I IFN activity and elevated numbers of LDGs (p=0.006 and p=0.001, respectively).ConclusionsNLR is elevated in patients with SLE as compared with healthy individuals, and is associated with key immunopathological events, including type I IFN activity and neutrophil activation. Neutrophil and lymphocyte count reflected different aspects of the pathogenesis of SLE. Further studies are needed to determine the causality of the associations.

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Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Journal of Virology ◽

10.1128/jvi.03275-14 ◽

2015 ◽

Vol 89 (8) ◽

pp. 4405-4420 ◽

Cited By ~ 15

Author(s):

Andrew K. Hastings ◽

John J. Erickson ◽

Jennifer E. Schuster ◽

Kelli L. Boyd ◽

Sharon J. Tollefson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Human Metapneumovirus ◽

Type I ◽

Type I Ifn ◽

Inhibitory Receptor ◽

Programmed Death ◽

Hmpv Infection ◽

Antigen Presenting

ABSTRACTType I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR−/−) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8+T cell response. HMPV-infected IFNAR−/−mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR−/−mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8+T cells of IFNAR−/−mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8+T cells of IFNAR−/−mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1lowdendritic cells (DCs), but not PD-L1highalveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8+T cell impairment.IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8+T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8+T cell impairment via PD-1–PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8+T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8+T cell impairment.

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DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

10.1101/197236 ◽

2017 ◽

Cited By ~ 1

Author(s):

Helen Loo Yau ◽

Ankur Chakravarthy ◽

Felipe Campos de Almeida ◽

David Allard ◽

Rajat Singhania ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cytolytic Activity ◽

Cell Tumor ◽

Type I ◽

Tumor Infiltration ◽

Activation Markers ◽

Viral Mimicry

AbstractRecent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

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Anti-Tumor Cytotoxicity of γδ T Cells Expanded from Blood Cells of Myeloma and Leukemia Patients Against Self Tumor Cells — Enhancement of the Anti-Tumor Cytotoxicity by Type I IFN, Dendritic Cells, and Activated αβ T Cells.

Blood ◽

10.1182/blood.v110.11.4762.4762 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4762-4762

Author(s):

Anri Saito ◽

Miwako Narita ◽

Norihiro Watanabe ◽

Nozomi Tochiki ◽

Noriyuki Satoh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Cells ◽

Hematological Malignancies ◽

Γδ T Cells ◽

Type I ◽

Type I Ifn ◽

Cd69 Expression ◽

Tumor Cytotoxicity ◽

Αβ T Cells

Abstract In order to establish an efficient gd T cell-mediated immunotherapy for hematological malignancies, we tried to clarify whether γδ T cells could be expanded from blood cells of patients with myeloma, lymphoma and acute leukemia by culture with zoledronate and a low dose of IL-2 and whether the expanded patients’ γδ T cells could kill tumor cells including self tumor cells with sparing normal clone cells. In addition, we explored the methods to enhance the anti-tumor cytotoxicity of the expanded γδ T cells by activating them with type I IFN, monocyte-derived dendritic cells (mo-DCs), or ab T cells. Although γδ T cells could be expanded in patients with myeloma, lymphoma and leukemia as well as normal persons, the amplification rates of gd T cells before and after the culture were varied from patient to patient in the patients with hematological malignancies. γδ T cells generated in patients with myeloma and lymphoma showed a potent cytotoxic ability against myeloma/lymphoma cell lines (RPMI8226, Daudi) as shown in γδ T cells generated in normal persons. In addition, γδ T cells generated in a patient with myeloma and acute leukemia showed a cytotoxic ability against self myeloma or leukemia cells freshly prepared from bone marrow. However, the same γδ T cells were not cytotoxic to normal lymphocytes of the patients. Then the expanded γδ T cells were stimulated with type I IFN, mo-DCs, or αβ T cells and the activation (CD69 expression) and cytotoxicity against tumor cells were examined. By the stimulation with type I IFN, the expression of CD69 and Trail of γδ T cells was increased and the cytotoxic ability of γδ T cells was enhanced at dose-dependent manner of type I IFN. CD69 expression on γδ T cells was enhanced by co-culture with both immature and mature mo-DCs in a cell-number-dependent fashion. CD69 expression was enhanced after the addition of mo-DCs of either autologous or allogeneic origin. Activation of γδ T cells with mo-DCs enhanced anti-tumor cytotoxicity of γδ T cells against RPMI8226 and CML blastic crisis cell line (C2F8) in an effector-to-target ratio-dependent manner. Although CD69 expression of γδ T cells was enhanced by the co-culture with allogeneic ab T cells, autologous ab T cells couldn’t activate γδ T cells. However, autologous ab T cells stimulated with IL-2 or PHA could induce the activation of γδ T cells. The activation of γδ T cells with stimulated αβ T cells required cell-to-cell interaction. These findings suggested that αβ T cells stimulated by allogeneic γδ T cells could activate the same allogeneic γδ T cells. The present data demonstrated that γδ T cells, which could be expanded in vitro from blood cells of the patients with myeloma, lymphoma and leukemia by culture with zoledronate and IL-2, possess an enough cytotoxic ability against tumor cells including self tumor cells with sparing normal cells. These findings suggested that in vitro generated patients’ γδ T cells could be applied to γδ T cell-mediated immunotherapy for hematological malignancies. Besides, potent γδ T cells activated by type I IFN, mo-DCs or activated αβ T cells were considered to be applicable for γδ T cell-mediated immunotherapy.

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IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo

Journal of Experimental Medicine ◽

10.1084/jem.20130901 ◽

2013 ◽

Vol 211 (1) ◽

pp. 105-120 ◽

Cited By ~ 81

Author(s):

Gabriel R. Starbeck-Miller ◽

Hai-Hui Xue ◽

John T. Harty

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Type I ◽

Type I Ifn ◽

Cellular Division ◽

High Affinity ◽

Cell Accumulation

TCR ligation and co-stimulation induce cellular division; however, optimal accumulation of effector CD8 T cells requires direct inflammatory signaling by signal 3 cytokines, such as IL-12 or type I IFNs. Although in vitro studies suggest that IL-12/type I IFN may enhance T cell survival or early proliferation, the mechanisms underlying optimal accumulation of CD8 T cells in vivo are unknown. In particular, it is unclear if disparate signal 3 cytokines optimize effector CD8 T cell accumulation by the same mechanism and how these inflammatory cytokines, which are transiently produced early after infection, affect T cell accumulation many days later at the peak of the immune response. Here, we show that transient exposure of CD8 T cells to IL-12 or type I IFN does not promote survival or confer an early proliferative advantage in vivo, but rather sustains surface expression of CD25, the high-affinity IL-2 receptor. This prolongs division of CD8 T cells in response to basal IL-2, through activation of the PI3K pathway and expression of FoxM1, a positive regulator of cell cycle progression genes. Thus, signal 3 cytokines use a common pathway to optimize effector CD8 T cell accumulation through a temporally orchestrated sequence of cytokine signals that sustain division rather than survival.

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