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1.
Cell Rep ; 38(3): 110259, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35045301

RESUMEN

CD21low age-associated or atypical memory B cells are autoantibody enriched and poised for plasma cell differentiation. These cells overaccumulate in chronic infections, autoimmune disease, and immunodeficiency, posing the question of what checkpoints normally oppose their accumulation. Here, we reveal a critical role for paralogous calcium-NFAT-regulated transcription factors EGR2 and EGR3 that are induced in self-reactive B cells. CD21low and B1 B cells lacking EGR2 and EGR3 accumulate and circulate in young mice in numbers 10- to 20-fold greater than normal and overexpress a large set of EGR2 ChIP-seq target genes, including known drivers of plasma cell differentiation. Most follicular B cells constitutively express Egr2 proportionally to surface IgM downregulation by self-antigens, and EGR2/3 deficiency abolishes this cardinal feature of B cell anergy. These results explain the cardinal features of B cell anergy, define a key transcriptional checkpoint repressing CD21low B cell formation, and inform how NFATC1 or EGR2 mutations promote B1 cell-derived chronic lymphocytic leukemias.


Asunto(s)
Linfocitos B/inmunología , Anergia Clonal/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 3 de la Respuesta de Crecimiento Precoz/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Autoinmunidad/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 3 de la Respuesta de Crecimiento Precoz/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Ratones , Receptores de Complemento 3d/inmunología
2.
Sci Immunol ; 6(65): eabj2132, 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34797692

RESUMEN

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against airborne pathogens. Tissue-specific differentiation and survival of alveolar macrophages rely on niche-derived factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor­ß (TGF-ß). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remain poorly understood. Here, we identify that the transcription factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-ß and GM-CSF in a PPAR-γ­dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for the regulation of lipids in the airways but crucial for the effective handling of the respiratory pathogen Streptococcus pneumoniae. Last, we show that EGR2 is required for repopulation of the alveolar niche after sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair after injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.


Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Macrófagos Alveolares/inmunología , Animales , Femenino , Humanos , Macrófagos Alveolares/patología , Masculino , Ratones , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/patología , Streptococcus pneumoniae/inmunología
3.
J Immunol ; 205(12): 3311-3318, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33188077

RESUMEN

IL-13 plays a critical role in mediating many biological processes responsible for allergic inflammation. Mast cells express Il13 mRNA and produce IL-13 protein in response to antigenic stimulation. Enhancers are essential in promoting gene transcription and are thought to activate transcription by delivering essential accessory cofactors to the promoter to potentiate gene transcription. However, enhancers mediating Il13 have not been identified. Furthermore, which Il13 enhancers detect signals triggered by antigenic stimulation have not yet been defined. In this study, we identified potential mouse Il13 enhancers using histone modification monomethylation at lysine residue 4 on histone 3 (H3K4me1) chromatin immunoprecipitation sequencing and acetylation at lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing. We used Omni-assay for transposase-accessible chromatin sequencing to determine which accessible regions within the potential Il13 enhancers that responded to IgE receptor crosslinking. We also demonstrated that the transcription factor cluster consisting of the NFATC2, STAT5, GATA2, AP1, and RUNX1 binding sites at the proximal Il13 enhancer and the transcription factor cluster consisting of the EGR2 binding site at the distal Il13 E+6.5 enhancer are critical in sensing the signals triggered by antigenic stimulation. Those enhancers, which are responsive to antigenic stimulation and are constitutively active, cooperate to generate greater transcriptional outputs. Our study reveals a novel mechanism underlying how antigenic stimulation induces robust Il13 mRNA expression in mouse mast cells.


Asunto(s)
Antígenos/inmunología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Factor de Transcripción GATA2/inmunología , Interleucina-13/inmunología , Mastocitos/inmunología , Factores de Transcripción NFATC/inmunología , Elementos de Respuesta/inmunología , Factor de Transcripción STAT5/inmunología , Factor de Transcripción AP-1/inmunología , Transcripción Genética/inmunología , Animales , Línea Celular , Mastocitos/citología , Ratones
4.
Cell Signal ; 76: 109800, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33011290

RESUMEN

NK1.1- CD4+ NKG2D+ T cells are a subpopulation of regulatory T cells that downregulate the functions of CD4+ T, CD8+ T, natural killer (NK) cells, and macrophages through TGF-ß1 production. Early growth response genes 2 (Egr2) and 3 (Egr3) maintain immune homeostasis by modulating T lymphocyte development, inhibiting effector T cell function, and promoting the induction of regulatory T cells. Whether Egr2 and Egr3 directly regulate TGF-ß1 transcription in NK1.1- CD4+ NKG2D+ T cells remains elusive. The expression levels of Egr2 and Egr3 were higher in NK1.1- CD4+ NKG2D+ T cells than in NK1.1- CD4+ NKG2D- T cells. Egr2 and Egr3 expression were remarkably increased after stimulating NK1.1- CD4+ NKG2D+ T cells with sRAE or α-CD3/sRAE. The ectopic expression of Egr2 or Egr3 resulted in the enhancement of TGF-ß1 expression, while knockdown of Egr2 or Egr3 led to the decreased expression of TGF-ß1 in NK1.1- CD4+ NKG2D+ T cells. Egr2 and Egr3 directly bound with the TGF-ß1 promoter as demonstrated by the electrophoretic mobility shift assay and dual-luciferase gene reporter assay. Furthermore, the Egr2 and Egr3 expression of NK1.1- CD4+ NKG2D+ T cells could be induced by the AP-1 and NF-κB transcriptional factors, but had no involvement with the activation of NF-AT and STAT3. In conclusion, Egr2 and Egr3 induced by AP-1 and NF-κB directly initiate TGF-ß1 transcription in NK1.1- CD4+ NKG2D+ T cells. This study indicates that manipulating Egr2 and Egr3 expression would potentiate or alleviate the regulatory function of NK1.1- CD4+ NKG2D+ T cells and this strategy could be used in the therapy for patients with autoimmune diseases or tumor.


Asunto(s)
Linfocitos T CD4-Positivos , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 3 de la Respuesta de Crecimiento Precoz/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Ratones , Ratones Transgénicos , FN-kappa B/inmunología , Neoplasias/inmunología
5.
J Immunol ; 201(5): 1452-1459, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30012846

RESUMEN

γδ NKT cells are neonatal-derived γδ T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of γδ NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote γδ NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating γδ NKT cell expansion. We observed a higher expression of Egr family genes in γδ NKT cells compared with the conventional γδ T cell population. Loss of function of Id3 caused an expansion of γδ NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient γδ NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated γδ NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient γδ NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2-double-deficient γδ NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2-Id3-E2A, which normally restricts the population size of γδ NKT cells by adjusting Egr2 dosage and c-Myc expression.


Asunto(s)
Proliferación Celular/fisiología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Regulación de la Expresión Génica/inmunología , Proteínas Inhibidoras de la Diferenciación/inmunología , Células T Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-myc/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteínas Inhibidoras de la Diferenciación/genética , Ratones , Ratones Noqueados , Células T Asesinas Naturales/citología , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc/inmunología , Proteínas Proto-Oncogénicas c-myc/genética , Receptores de Antígenos de Linfocitos T gamma-delta
6.
Nat Commun ; 9(1): 2650, 2018 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-29985393

RESUMEN

During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells.


Asunto(s)
Diferenciación Celular/inmunología , Células T Asesinas Naturales/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Timocitos/inmunología , Animales , Sitios de Unión , Diferenciación Celular/genética , Células Cultivadas , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Perfilación de la Expresión Génica/métodos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/inmunología , Factores de Transcripción NFATC/metabolismo , Células T Asesinas Naturales/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/genética , Subgrupos de Linfocitos T/metabolismo , Timocitos/citología , Timocitos/metabolismo
7.
Front Immunol ; 9: 340, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29535721

RESUMEN

Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4+CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+CD25+ Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells. Lymphocyte activation gene 3 (LAG3) and CD49b are reliable cell surface markers for Tr1 cells. CD4+CD25-LAG3+ Tregs (LAG3+ Tregs) develop in the periphery and produce a large amount of IL-10. LAG3+ Tregs characteristically express the early growth response gene 2 (Egr2), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although Egr2 was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that Egr2 plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3+ Tregs. Intriguingly, forced expression of Egr2 converts naive CD4+ T cells into IL-10-producing Tregs that highly express LAG3. Among the four Egr gene family members, Egr3 is thought to compensate for the function of Egr2. Recently, we reported that LAG3+ Tregs suppress humoral immune responses via transforming growth factor ß3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of Egr2 in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.


Asunto(s)
Antígenos CD/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes/embriología , Enfermedades Autoinmunes/patología , Anergia Clonal , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad Humoral , Linfocitos T Reguladores/patología , Proteína del Gen 3 de Activación de Linfocitos
8.
Immun Inflamm Dis ; 6(2): 221-233, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29314730

RESUMEN

INTRODUCTION: Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto-reactive T cells do not display hyper proliferation, but inflammatory phenotypes. METHODS: We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction. RESULTS: In the absence of Egr2 and 3, T cell tolerance, as measured by impaired proliferation and production of IL2, can still be induced, but tolerant T cells produced high levels of inflammatory cytokines. Egr2 and 3 regulate expression of differentiation repressors and directly inhibit T-bet function in T cells. Indeed, decreased expression of differentiation repressors, such as Id3 and Tcf1, and increased expression of inflammatory transcription factors, such as RORγt and Bhlhe40 were found in Egr2/3 deficient T cells under tolerogenic conditions. In addition, T-bet was co-expressed with Egr2 in tolerant T cells and Egr2/3 defects leads to production of high levels of IFNγ in tolerant T cells. CONCLUSIONS: Our findings demonstrated that despite impaired proliferation and IL2 production, tolerant T cells can display inflammatory responses in response to antigen stimulation and this is controlled at least partly by Egr2 and 3.


Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 3 de la Respuesta de Crecimiento Precoz/inmunología , Tolerancia Inmunológica/genética , Inflamación/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Autoantígenos/inmunología , Trasplante de Médula Ósea , Antígenos CD2/inmunología , Antígenos CD2/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/metabolismo , Enterotoxinas/administración & dosificación , Enterotoxinas/inmunología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Técnicas de Sustitución del Gen , Humanos , Receptores de Hialuranos/inmunología , Receptores de Hialuranos/metabolismo , Interleucina-2/inmunología , Interleucina-2/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Transducción de Señal/genética , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Quimera por Trasplante/inmunología
9.
Cell Rep ; 20(3): 600-612, 2017 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-28723564

RESUMEN

The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner. At the molecular level, GCN5 is a specific lysine acetyltransferase of early growth responsive gene 2 (EGR2), a transcription factor required for iNKT cell development. GCN5-mediated acetylation positively regulated EGR2 transcriptional activity, and both genetic and pharmacological GCN5 suppression specifically inhibited the transcription of EGR2 target genes in iNKT cells, including Runx1, promyelocytic leukemia zinc finger protein (PLZF), interleukin (IL)-2Rb, and T-bet. Therefore, our study revealed GCN5-mediated EGR2 acetylation as a molecular mechanism that regulates iNKT development.


Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Células T Asesinas Naturales/inmunología , Factores de Transcripción p300-CBP/inmunología , Acetilación , Animales , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/inmunología , Ratones , Ratones Transgénicos , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Factores de Transcripción p300-CBP/genética
10.
J Biol Chem ; 292(11): 4686-4699, 2017 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-28130449

RESUMEN

A growing understanding of the bone remodeling process suggests that inflammation significantly contributes to the pathogenesis of osteoporosis. T cells and various cytokines contribute majorly to the estrogen deficiency-induced bone loss. Recent studies have identified the IL-12 cytokine family as consisting of pro-inflammatory IL-12 and IL-23 and the anti-inflammatory IL-27 and IL-35 cytokines. IL-27 exerts protective effects in autoimmune diseases like experimental autoimmune encephalomyelitis; however, its role in the pathogenesis of osteoporosis remains to be determined. In this report, we study the effect of IL-27 supplementation on ovariectomized estrogen-deficient mice on various immune and skeletal parameters. IL-27 treatment in ovariectomized mice suppressed Th17 cell differentiation by inhibiting transcription factor RORγt. Supplementation of IL-27 activates Egr-2 to induce IL-10 producing Tr1 cells. IL-27 treatment prevented the loss of trabecular micro-architecture and preserved cortical bone parameters. IL-27 also inhibited osteoblast apoptosis through increased Egr-2 expression, which induces anti-apoptotic factors like MCL-1. IL-27 suppressed osteoclastogenesis in an Egr-2-dependent manner that up-regulates Id2, the repressor of the receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis. Additionally, these results were corroborated in female osteoporotic subjects where we found decreased serum IL-27 levels along with reduced Egr-2 expression. Our study forms a strong basis for using humanized IL-27 toward the treatment of post-menopausal osteoporosis.


Asunto(s)
Antiinflamatorios/uso terapéutico , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Interleucina-27/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/inmunología , Antiinflamatorios/metabolismo , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/metabolismo , Huesos/patología , Células Cultivadas , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Estrógenos/genética , Femenino , Eliminación de Gen , Humanos , Interleucina-10/inmunología , Interleucina-27/genética , Interleucina-27/inmunología , Ratones , Ratones Endogámicos BALB C , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/inmunología , Osteoclastos/patología , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/patología , ARN Mensajero/genética , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/patología
11.
J Leukoc Biol ; 101(5): 1221-1231, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28096300

RESUMEN

Compared with CD4+25+ regulatory T cells (Tregs), the mechanisms for natural, polyclonal CD8+25+ Treg immune suppression have been significantly less studied. We previously showed that polyclonal T cells can acquire antigen-specific targeting activity through arming with exosomal peptide-MHC (pMHC). In this study, we assessed the suppressive effect of CD8+25+ Tregs or CD8+25+ Tregs armed with ovalbumin (OVA)-specific exosomes on other immune cells and OVA-specific dendritic cell (DCOVA)-stimulated antitumor immunity. We demonstrate that CD8+25+ Tregs inhibit T cell proliferation in vitro in a cell contact-dependent fashion but independent of the expression of immunosuppressive IL-10, TGF-ß, and CTLA-4. CD8+25+ Tregs anergize naïve T cells upon stimulation by up-regulating T cell anergy-associated Egr2 and down-regulating IL-2 production. Tregs also anergize DCs by preventing DC maturation through the down-regulation of Iab, CD80, CD86, and inflammatory cytokines, leading to defects in T cell stimulation. Moreover, CD8+25+ Tregs inhibit CTLs through inducing CTL death via perforin-mediated apoptosis and through reducing effector CTL cytotoxic activity via down-regulating CTL perforin-production and degranulation. In addition, we show that CD8+25+ Tregs suppress DCOVA-stimulated CTL responses in priming and effector phases and inhibit immunity against OVA-expressing CCLOVA lung cancer. Remarkably, polyclonal CD8+25+ Tregs armed with OVA-specific exosomal pMHC class-II (pMHC-II), or pMHC class-I (pMHC-I) complexes exert their enhanced inhibition of CTL responses in the priming and the effector phases, respectively. Taken together, our investigation reveals that assigning antigen specificity to nonspecific polyclonal CD8+25+ Tregs for enhanced immune suppression can be achieved through exosomal pMHC arming. This principle may have a great effect on Treg-mediated immunotherapy of autoimmune diseases.


Asunto(s)
Células Dendríticas/inmunología , Exosomas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Proliferación Celular , Anergia Clonal , Citotoxicidad Inmunológica , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Exosomas/química , Regulación de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trasplante de Neoplasias , Ovalbúmina/farmacología , Cultivo Primario de Células , Transducción de Señal , Análisis de Supervivencia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología
12.
Proc Natl Acad Sci U S A ; 113(50): E8131-E8140, 2016 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-27911796

RESUMEN

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25-LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-ß3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-ß3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25-LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-ß3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25-LAG3+ cells or treatment with a TGF-ß3-expressing vector. Intriguingly, latent TGF-ß binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-ß3 production from CD4+CD25-LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-ß3 production by CD4+CD25-LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.


Asunto(s)
Autoinmunidad , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 3 de la Respuesta de Crecimiento Precoz/inmunología , Proteínas de Unión a TGF-beta Latente/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta3/biosíntesis , Inmunidad Adaptativa , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Diferenciación Celular , Modelos Animales de Enfermedad , Proteína 2 de la Respuesta de Crecimiento Precoz/deficiencia , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/deficiencia , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Centro Germinal/inmunología , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/patología
13.
Rheumatology (Oxford) ; 55(suppl 2): ii76-ii81, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27856665

RESUMEN

SLE is an autoimmune disease characterized by multiple organ damage mediated by autoantibodies and autoreactive T cells. Approaches utilizing genetically engineered mice as well as genome-wide association studies have identified a number of lupus-related genes. Recently, early growth response gene 2 (Egr2) and Egr3 have emerged as regulatory molecules that suppress excessive immune responses. Mice deficient for Egr2 and Egr3 develop a lupus-like disease with dysregulated activation of effector T cells. Furthermore, Egr2 and Egr3 confer suppressive activity to CD4+ T cells and regulate the production of inhibitory cytokines such as IL-10 and TGF-ß1. These findings may have implications for a wide range of immune-related pathologies and suggest the possibility that efforts exploiting Egr2 and Egr3 could aid in the development of therapeutic applications. This review summarizes the recent advances regarding the roles of Egr2 and Egr3 on T cells in the control of autoimmunity.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 3 de la Respuesta de Crecimiento Precoz/inmunología , Lupus Eritematoso Sistémico/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Humanos , Interleucina-10/inmunología , Interleucina-17/inmunología , Lupus Eritematoso Sistémico/genética , Ratones , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/inmunología
14.
J Immunol ; 196(3): 1102-7, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26718337

RESUMEN

Guillain-Barré syndrome (GBS) is an immune-mediated peripheral neuropathy. The goal of this research was the identification of biomarkers associated with recovery from GBS. In this study, we compared the transcriptome of PBMCs from a GBS patient and her healthy twin to discover possible correlates of disease progression and recovery. The study was then extended using GBS and spinal cord injury unrelated patients with similar medications and healthy individuals. The early growth response gene-2 (EGR2) was upregulated in GBS patients during disease recovery. The results provided evidence for the implication of EGR2 in GBS and suggested a role for EGR2 in the regulation of IL-17, IL-22, IL-28A, and TNF-ß cytokines in GBS patients. These results identified biomarkers associated with GBS recovery and suggested that EGR2 overexpression has a pivotal role in the downregulation of cytokines implicated in the pathophysiology of this acute neuropathy.


Asunto(s)
Biomarcadores/análisis , Proteína 2 de la Respuesta de Crecimiento Precoz/biosíntesis , Síndrome de Guillain-Barré/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/biosíntesis , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Recuperación de la Función , Transcriptoma , Regulación hacia Arriba , Adulto Joven
15.
Nat Commun ; 6: 8698, 2015 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-26507712

RESUMEN

Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell-mediated inflammation.


Asunto(s)
Antígenos CD28/inmunología , Proteínas de Ciclo Celular/genética , Anergia Clonal , Regulación hacia Abajo , Interleucina-2/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Linfocitos T/inmunología , Animales , Antígenos CD28/genética , Proteínas de Ciclo Celular/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Interleucina-2/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
16.
Int Immunopharmacol ; 28(2): 866-74, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25864617

RESUMEN

Recent evidence has suggested that miRNA is implicated in the immune response of allergic and inflammatory diseases. However, little is known about its role in the mechanism that underlies the establishment of pro-allergic DCs in allergic rhinitis is not fully understood. This study assessed whether and how microRNA (miR)-106b regulates the pro-allergic properties of DCs upon allergen stimulation in vitro. Bone marrow-derived dendritic cells (BMDCs) were generated and stimulated with ovalbumin (OVA) to identify the miRNA expression profile. After transfection with miR-106b mimics and inhibitors OVA-activated BMDCs were further evaluated for surface marker expression using flow cytometry, cytokine production using ELISA and subsequent effects on Th2 cell polarisation using flow cytometry. Moreover, the upstream controllers and potential target proteins of miR-106b were examined in a western blot analysis. Results showed that MiR-106b expression was significantly inhibited in activated BMDCs upon OVA stimulation (p<0.05). Surface marker expression (e.g., MHC class II, CD80 and CD86) was significantly upregulated after the transfection of an miR-106b inhibitor (p<0.05), and the proportion of GATA-3(+) T cells was significantly increased among CD4(+) T cells that were cocultured with miR-106b inhibitor-pretreated BMDCs (p<0.05). Conversely, IL-12 production from OVA-activated BMDCs and the proportion of T-bet(+) T cells increased significantly in a coculture of CD4(+) T cells and miR-106b mimics-transfected BMDCs (p<0.05). The early growth response (Egr)-2 was identified via luciferase reporter assays as a target gene of miR-106b, and significant Egr-2 upregulation was observed in OVA-activated BMDCs following transfection with a miR-106b inhibitor (p<0.05). In conclusion, our results suggest that miR-106b negatively regulates the pro-allergic properties of BMDCs and subsequent Th2 polarisation upon OVA stimulation and might represent a promising therapeutic target for allergic inflammation.


Asunto(s)
Células Dendríticas/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , MicroARNs/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Células Cultivadas , Hipersensibilidad/inmunología , Masculino , Ratones Endogámicos BALB C , Ovalbúmina/inmunología
17.
Artículo en Japonés | MEDLINE | ID: mdl-25765691

RESUMEN

Autoantibodies are associated with various autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoantibody-associated autoimmune disease which affects multiple organs. Although both genetic and environmental factors are implicated in lupus pathogenesis, the etiology of the disease remains elusive. The discovery of CD4(+)CD25(+) regulatory T cells (Tregs) that characteristically express forkhead box p3 (Foxp3) gene have greatly advanced our understanding of immune systems in autoimmune diseases. CD4(+) Tregs can be classified into two main populations: thymus-derived naturally occurring Tregs (nTregs) and induced Tregs (iTregs) generated from CD4(+)CD25(-) precursors in the periphery. Recently, accumulating evidence suggests that these Tregs play important roles in the regulation of humoral immune responses. In this review, we discuss recent findings on the role of Tregs in SLE.


Asunto(s)
Autoanticuerpos/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD/inmunología , Linfocitos T CD4-Positivos , Modelos Animales de Enfermedad , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Factores de Transcripción Forkhead/inmunología , Humanos , Inmunidad Humoral/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Lupus Eritematoso Sistémico/genética , Ratones , Linfocitos T Reguladores/clasificación , Proteína del Gen 3 de Activación de Linfocitos
18.
Eur J Immunol ; 45(2): 480-91, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25382658

RESUMEN

Anergic T cells can survive for long time periods passively in a hyporesponsive state without obvious active functions. Thus, the immunological reason for their maintenance is unclear. Here, we induced peptide-specific anergy in T cells from mice by coculturing these cells with immature murine dendritic cells (DCs). We found that these anergic, nonsuppressive IL-10(-) Foxp3(-) CTLA-4(+) CD25(low) Egr2(+) T cells could be converted into suppressive IL-10(+) Foxp3(-) CTLA-4(+) CD25(high) Egr2(+) cells resembling type-1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF-ß during anergy induction favored Foxp3(+) Treg-cell induction, while TGF-ß had little effect when added to the second stimulation. Expression of both CD28 and CTLA-4 molecules on anergic T cells was required to allow their conversion into Tr1-like cells. Suppressor activity was enabled via CD28-mediated CD25 upregulation, acting as an IL-2 sink, together with a CTLA-4-mediated inhibition of NFATc1/α activation to shut down IL-2-mediated proliferation. Together, these data provide evidence and mechanistical insights into how persistent anergic T cells may serve as a resting memory pool for Tr1-like cells.


Asunto(s)
Antígenos CD28/genética , Antígeno CTLA-4/genética , Anergia Clonal , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/genética , Interleucina-10/genética , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD28/inmunología , Antígeno CTLA-4/inmunología , Comunicación Celular , Diferenciación Celular , Técnicas de Cocultivo , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Interleucina-10/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/inmunología , Transducción de Señal , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/farmacología
19.
Eur J Immunol ; 44(12): 3646-57, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25236978

RESUMEN

CD1d-restricted NKT cells represent a unique lineage of immunoregulatory T cells that are divided into two groups, type I and type II, based on their TCR usage. Because there are no specific tools to identify type II NKT cells, little is known about their developmental requirements and functional regulation. In our previous study, we showed that signaling lymphocytic activation molecule associated protein (SAP) is essential for the development of type II NKT cells. Here, using a type II NKT-cell TCR transgenic mouse model, we demonstrated that CD1d-expressing hematopoietic cells, but not thymic epithelial cells, meditate efficient selection of type II NKT cells. Furthermore, we showed that SAP regulates type II NKT-cell development by controlling early growth response 2 protein and promyelocytic leukemia zinc finger expression. SAP-deficient 24αß transgenic T cells (24αß T cells) exhibited an immature phenotype with reduced Th2 cytokine-producing capacity and diminished cytotoxicity to CD1d-expressing lymphoma cells. The impaired IL-4 production by SAP-deficient 24αß T cells was associated with reduced IFN regulatory factor 4 and GATA-3 induction following TCR stimulation. Collectively, these data suggest that SAP is critical for regulating type II NKT cell responses. Aberrant responses of these T cells may contribute to the immune dysregulation observed in X-linked lymphoproliferative disease caused by mutations in SAP.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Inmunidad Celular , Interleucina-4/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Linfoma/inmunología , Células T Asesinas Naturales/inmunología , Animales , Antígenos CD1d/genética , Antígenos CD1d/inmunología , Línea Celular Tumoral , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Interleucina-4/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/inmunología , Linfoma/genética , Linfoma/patología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/patología , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria
20.
J Immunol ; 192(6): 2643-50, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24532578

RESUMEN

Development of effective immune therapies for cancer patients requires better understanding of hurdles that prevent the generation of effective antitumor immune responses. Administration of α-galactosylceramide (α-GalCer) in animals enhances antitumor immunity via activation of the invariant NKT (iNKT) cells. However, repeated injections of α-GalCer result in long-term unresponsiveness or anergy of iNKT cells, severely limiting its efficacy in tumor eradication. The mechanisms leading to iNKT cell anergy remain poorly understood. We report in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a crucial role in iNKT cell anergy. Deficiency of TSC1 in iNKT cells results in resistance to α-GalCer-induced anergy, manifested by increased expansion of and cytokine production by iNKT cells in response to secondary Ag stimulation. It is correlated with impaired upregulation of programmed death-1, Egr2, and Grail. Moreover, TSC1-deficient iNKT cells display enhanced antitumor immunity in a melanoma lung metastasis model. Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune therapy.


Asunto(s)
Anergia Clonal/inmunología , Melanoma Experimental/inmunología , Células T Asesinas Naturales/inmunología , Esclerosis Tuberosa/inmunología , Animales , Línea Celular Tumoral , Citocinas/inmunología , Citocinas/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Homeostasis/genética , Homeostasis/inmunología , Immunoblotting , Inmunoterapia Adoptiva , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/trasplante , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismo
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