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1.
JCI Insight ; 6(14)2021 07 22.
Article in English | MEDLINE | ID: mdl-34156979

ABSTRACT

Estrogen-related receptor γ (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls Tregs through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Tregs, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Tregs presented an impaired differentiation into follicular Tregs that enhanced follicular helper T cells' responses. Mechanistically, Esrrg-deficient Tregs presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Tregs exhibited decreased phosphatidylinositol and TGF-ß signaling pathways and increased mTOR complex 1 activation. We found that the expression of human ESRRG, which is high in Tregs, was lower in CD4+ T cells from patients with lupus than in healthy controls. Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Tregs, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.


Subject(s)
Lupus Erythematosus, Systemic/genetics , Mitochondria/pathology , Receptors, Estrogen/deficiency , Receptors, Estrogen/genetics , T-Lymphocytes, Regulatory/immunology , Animals , Disease Models, Animal , Female , Gene Knockdown Techniques , Humans , Jurkat Cells , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Mice , Mitochondria/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism
2.
Clin Immunol ; 221: 108602, 2020 12.
Article in English | MEDLINE | ID: mdl-33007439

ABSTRACT

OBJECTIVE: This study performed an integrated analysis of the cellular and transcriptional differences in peripheral immune cells between patients with Systemic Lupus Erythematosus (SLE) and healthy controls (HC). METHODS: Peripheral blood was analyzed using standardized flow cytometry panels. Transcriptional analysis of CD4+ T cells was performed by microarrays and Nanostring assays. RESULTS: SLE CD4+ T cells showed an increased expression of oxidative phosphorylation and immunoregulatory genes. SLE patients presented higher frequencies of activated CD38+HLA-DR+ T cells than HC. Hierarchical clustering identified a group of SLE patients among which African Americans were overrepresented, with highly activated T cells, and higher frequencies of Th1, Tfh, and plasmablast cells. T cell activation was positively correlated with metabolic gene expression in SLE patients but not in HC. CONCLUSIONS: SLE subjects presenting with activated T cells and a hyperactive metabolic signature may represent an opportunity to correct aberrant immune activation through targeted metabolic inhibitors.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lupus Erythematosus, Systemic/immunology , T-Lymphocyte Subsets/immunology , Adult , Aged , Female , Gene Expression , Humans , Immunophenotyping , Lupus Erythematosus, Systemic/genetics , Middle Aged , Young Adult
3.
J Immunol ; 203(2): 338-348, 2019 07 15.
Article in English | MEDLINE | ID: mdl-31160534

ABSTRACT

In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4+ T cell activation. In this study, we report that in CD4+ T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-α treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4+ T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Hypoglycemic Agents/therapeutic use , Interferon Type I/antagonists & inhibitors , Metformin/therapeutic use , Adult , Aged , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Leukocytes, Mononuclear/drug effects , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation/drug effects , Male , Middle Aged , Oxidative Phosphorylation/drug effects , Signal Transduction/drug effects , Young Adult
4.
Nat Commun ; 9(1): 4369, 2018 10 22.
Article in English | MEDLINE | ID: mdl-30348969

ABSTRACT

Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating TFH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of TFH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific TFH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune TFH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune TFH cells and exogenous antigen-specific TFH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive TFH cells while preserving protective immunity against pathogens.


Subject(s)
Glucose/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , Amino Acids/metabolism , Animals , Autoantibodies/metabolism , Autoimmunity/physiology , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Mice
5.
Curr Opin Rheumatol ; 29(5): 434-441, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28537986

ABSTRACT

PURPOSE OF REVIEW: The complexity and heterogeneity of the clinical presentation in systemic lupus of erythematosus (SLE), combined to the inherent limitations of clinical research, have made it difficult to investigate the cause of this disease directly in patients. Various mouse models have been developed to dissect the cellular and genetic mechanisms of SLE, as well as to identify therapeutic targets and to screen treatments. The purpose of this review is to summarize the major spontaneous and induced mouse models of SLE and to provide an update on the major advances they have contributed to the field. RECENT FINDINGS: Mouse models of SLE have continued to contribute to understand the cellular, signaling and metabolic mechanisms contributing to the disease and how targeting these pathways can provide therapeutic targets. Whenever possible, we discuss the advantage of using one model over the others to test a specific hypothesis. SUMMARY: Spontaneous and induced models of lupus models are useful tools for the study of the cause of the disease, identify therapeutic targets and screen treatments in preclinical studies. Each model shares specific subsets of attributes with the disease observed in humans, which provides investigators a tool to tailor to their specific needs.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Genetic Testing/methods , Genetic Therapy/methods , Lupus Erythematosus, Systemic , Animals , Disease Models, Animal , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/therapy
6.
Mol Immunol ; 85: 148-154, 2017 05.
Article in English | MEDLINE | ID: mdl-28257976

ABSTRACT

PBX1-d is novel splice isoform of pre-B-cell leukemia homeobox 1 (PBX1) that lacks its DNA-binding and Hox-binding domains, and functions as a dominant negative. We have shown that PBX1-d expression in CD4+ T cells is associated with systemic lupus erythematosus (SLE) in a mouse model as well as in human subjects. More specifically, PBX1-d expression leads to the production of autoreactive activated CD4+ T cells, a reduced frequency and function of Foxp3+ regulatory T (Treg) cells and an expansion of follicular helper T (Tfh) cells. Very little is known about the function of PBX1 in T cells, except that it directly regulates the expression of miRNAs associated with Treg and Tfh homeostasis. In the present study, we show that PBX1 directly regulated the expression of CD44, a marker of T cell activation. Two PBX1 binding sites in the promoter directly regulated CD44 expression, with PBX1-d driving a higher expression than the normal isoform PBX1-b. In addition, mutations in each of the two binding sites had different effects of PBX1-b and PBX1-d. Finally, we showed that an enhanced recruitment of co-factor MEIS by PBX1-d over PBX1-b, while there was no difference for co-factor PREP1 recruitment. Therefore, this study demonstrates that the lupus-associated PBX1-d isoform directly transactivates CD44, a marker of CD44 activation and memory, and that it has different DNA binding and co-factor recruitment relative to the normal isoform. Taken together, these results confirm that PBX1 directly regulates genes related to T cell activation and shows that the lupus-associated isoform PBX1-d has unique molecular functions.


Subject(s)
DNA-Binding Proteins/genetics , Hyaluronan Receptors/biosynthesis , Lupus Erythematosus, Systemic/genetics , Lymphocyte Activation/genetics , Proto-Oncogene Proteins/genetics , Blotting, Western , CD4-Positive T-Lymphocytes/immunology , Chromatin Immunoprecipitation , DNA-Binding Proteins/metabolism , Flow Cytometry , Gene Expression Regulation/genetics , Genetic Predisposition to Disease/genetics , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/immunology , Immunoprecipitation , Jurkat Cells , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Activation/immunology , Mutagenesis, Site-Directed , Pre-B-Cell Leukemia Transcription Factor 1 , Protein Isoforms/genetics , Protein Isoforms/immunology , Protein Isoforms/metabolism , Proto-Oncogene Proteins/metabolism , Real-Time Polymerase Chain Reaction
7.
Curr Rheumatol Rep ; 18(11): 66, 2016 11.
Article in English | MEDLINE | ID: mdl-27709413

ABSTRACT

Cellular metabolism represents a newly identified checkpoint of effector functions in the immune system. A solid body of work has characterized the metabolic requirements of normal T cells during activation and differentiation into polarized effector subsets. Similar studies have been initiated to characterize the metabolic requirements for B cells and myeloid cells. Only a few studies though have characterized the metabolism of immune cells in the context of autoimmune diseases. Here, we review what is known on the altered metabolic patterns of CD4+ T cells, B cells, and myeloid cells in lupus patients and lupus-prone mice and how they contribute to lupus pathogenesis. We also discuss how defects in immune metabolism in lupus can be targeted therapeutically.


Subject(s)
Autoimmunity/immunology , B-Lymphocytes/metabolism , Lupus Erythematosus, Systemic/immunology , T-Lymphocytes/metabolism , Humans , Lupus Erythematosus, Systemic/metabolism
8.
Crit Rev Immunol ; 36(1): 75-98, 2016.
Article in English | MEDLINE | ID: mdl-27480903

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organ damage is mediated by pathogenic autoantibodies directed against nucleic acids and protein complexes. Studies in SLE patients and in mouse models of lupus have implicated virtually every cell type in the immune system in the induction or amplification of the autoimmune response as well as the promotion of an inflammatory environment that aggravates tissue injury. Here, we review the contribution of CD4+ T cells, B cells, and myeloid cells to lupus pathogenesis and then discuss alterations in the metabolism of these cells that may contribute to disease, given the recent advances in the field of immunometabolism.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Lupus Erythematosus, Systemic/immunology , Myeloid Cells/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , Humans , Lupus Erythematosus, Systemic/metabolism , Myeloid Cells/metabolism
9.
J Immunol ; 197(2): 458-69, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27296664

ABSTRACT

Pbx1 controls chromatin accessibility to a large number of genes and is entirely conserved between mice and humans. The Pbx1-d dominant-negative isoform is more frequent in CD4(+) T cells from lupus patients than from healthy controls. Pbx1-d is associated with the production of autoreactive T cells in mice carrying the Sle1a1 lupus-susceptibility locus. Transgenic (Tg) expression of Pbx1-d in CD4(+) T cells reproduced the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4(+) T cells and impaired Foxp3(+) regulatory T cell (Treg) homeostasis. Pbx1-d-Tg expression also expanded the number of follicular helper T cells (TFHs) in a cell-intrinsic and Ag-specific manner, which was enhanced in recall responses and resulted in Th1-biased Abs. Moreover, Pbx1-d-Tg CD4(+) T cells upregulated the expression of miR-10a, miR-21, and miR-155, which were implicated in Treg and follicular helper T cell homeostasis. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation and promoting TFHs at the expense of Tregs. In addition, our results identify Pbx1 as a novel regulator of CD4(+) T cell effector function.


Subject(s)
Cell Differentiation/immunology , DNA-Binding Proteins/immunology , Lupus Erythematosus, Systemic/immunology , Proto-Oncogene Proteins/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Flow Cytometry , Homeodomain Proteins/immunology , Humans , Immunohistochemistry , Mice , Mice, Transgenic , Polymerase Chain Reaction , Pre-B-Cell Leukemia Transcription Factor 1 , Transcription Factors/immunology
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