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1.
J Immunol ; 207(2): 363-370, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34644259

RESUMO

T cell development occurs in the thymus, where uncommitted progenitors are directed into a range of sublineages with distinct functions. The goal is to generate a TCR repertoire diverse enough to recognize potential pathogens while remaining tolerant of self. Decades of intensive research have characterized the transcriptional programs controlling critical differentiation checkpoints at the population level. However, greater precision regarding how and when these programs orchestrate differentiation at the single-cell level is required. Single-cell RNA sequencing approaches are now being brought to bear on this question, to track the identity of cells and analyze their gene expression programs at a resolution not previously possible. In this review, we discuss recent advances in the application of these technologies that have the potential to yield unprecedented insight to T cell development.


Assuntos
Diferenciação Celular/imunologia , Linfócitos T/imunologia , Animais , Humanos , Análise de Sequência de RNA/métodos , Timo/imunologia
2.
Front Immunol ; 12: 645277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335563

RESUMO

Circulating T helper cells with a type 17-polarized phenotype (TH17) and expansion of aquaporin-4 (AQP4)-specific T cells are frequently observed in patients with neuromyelitis optica spectrum disorder (NMOSD). However, naive T cell populations, which give rise to T helper cells, and the primary site of T cell maturation, namely the thymus, have not been studied in these patients. Here, we report the alterations of naive CD4 T cell homeostasis and the changes in thymic characteristics in NMOSD patients. Flow cytometry was performed to investigate the naive CD4+ T cell subpopulations in 44 NMOSD patients and 21 healthy controls (HC). On immunological evaluation, NMOSD patients exhibited increased counts of CD31+thymic naive CD4+ T cells and CD31-cental naive CD4+ T cells along with significantly higher fraction and absolute counts of peripheral blood CD45RA+ CD62L+ naive CD4+ T cells. Chest computed tomography (CT) images of 60 NMOSD patients and 65 HCs were retrospectively reviewed to characterize the thymus in NMOSD. Thymus gland of NMOSD patients exhibited unique morphological characteristics with respect to size, shape, and density. NMOSD patients showed exacerbated age-dependent thymus involution than HC, which showed a significant association with disease duration. These findings broaden our understanding of the immunological mechanisms that drive severe disease in NMOSD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Neuromielite Óptica/imunologia , Timo/imunologia , Adulto , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologia , Estudos Retrospectivos , Timo/patologia
3.
Front Immunol ; 12: 616215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447366

RESUMO

Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2 -/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Insulina/farmacologia , Precursores de Proteínas/farmacologia , Receptores Fc/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Timo/imunologia , Administração Oral , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Insulina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Precursores de Proteínas/genética , Receptores Fc/genética , Proteínas Recombinantes de Fusão/genética
4.
Front Immunol ; 12: 669943, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211466

RESUMO

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII-/- mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.


Assuntos
Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Tolerância Imunológica , Imunodeficiência Combinada Severa/imunologia , Timo/imunologia , Adolescente , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , América do Norte , Proteoma , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/cirurgia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timócitos , Timo/metabolismo , Transcriptoma , Adulto Jovem
5.
Front Immunol ; 12: 668528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220815

RESUMO

The microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs) play a non-redundant role in the generation of functionally diverse and self-tolerant T cells. The role of TECs during the first weeks of the murine postnatal life is particularly challenging due to the significant augment in T cell production. Here, we critically review recent studies centered on the timely coordination between the expansion and maturation of TECs during this period and their specialized role in T cell development and selection. We further discuss how aging impacts on the pool of TEC progenitors and maintenance of functionally thymic epithelial microenvironments, and the implications of these chances in the capacity of the thymus to sustain regular thymopoiesis throughout life.


Assuntos
Diferenciação Celular , Proliferação de Células , Células Epiteliais/fisiologia , Células-Tronco/fisiologia , Timo/fisiologia , Fatores Etários , Animais , Microambiente Celular , Células Epiteliais/imunologia , Humanos , Tolerância a Antígenos Próprios , Células-Tronco/imunologia , Linfócitos T/imunologia , Timócitos/imunologia , Timo/imunologia
6.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34225443

RESUMO

Myasthenia Gravis (MG) is an autoimmune disease that affects neuromuscular junctions and is characterized by muscle weakness as a result of autoantibodies against certain proteins. As a heterogeneous disorder, MG presents with different types, including neonatal, ocular and generalized in both juveniles and adults. Different types of antibodies serve a role in how MG presents. The main biological characteristic of MG is the production of antibodies against the muscular acetylcholine receptor; however, other types of antibody have been associated with the disorder. The role of the thymus gland has been established and thymectomy is a possible treatment of the disease, along with traditional medication such as pyridostigmine bromide (Mestinon) and immunosuppresants. In recent years, steps have been made towards developing more sensitive diagnostic methods. Additionally, novel treatments have demonstrated promising results. Developing new assays may lead to an increased understanding of the disease and to unravelling the genetic pathway that leads to the development of neuromuscular diseases.


Assuntos
Autoimunidade , Epigênese Genética , Miastenia Gravis/genética , Miastenia Gravis/imunologia , Autoanticorpos/imunologia , Epigênese Genética/imunologia , Genômica , Humanos , Miastenia Gravis/terapia , Manejo da Obesidade/métodos , Fenótipo , Timo/imunologia , Timo/cirurgia
7.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205753

RESUMO

The mechanisms through which maternal immunization can modulate offspring thymic maturation of lymphocytes are not fully understood. Here, we aimed to evaluate whether maternal OVA-immunization can inhibit the maturation of IL-17-producing γδT cells in offspring thymus, and if this mechanism has epigenetic implications mediated by microRNAs (miRNAs) expression. Wild-type (WT) C57BL/6 females were immunized with OVA in Alum or Alum alone and were mated with normal WT males. Evaluating their offspring thymus at 3 or 20 days old (d.o.), we observed that maternal OVA immunization could inhibit the thymic frequency of offspring CD27- and IL-17+ γδT cells at the neonatal and until 20 days old. Furthermore, we evaluated the expression of function-related γ and δ variable γδTCR chains (Vγ1, Vγ2, Vγ3, Vδ4, and Vδ6.3), observing that maternal OVA-immunization inhibits Vγ2 chains expression. The small RNAs (sRNAs), particularly miRNAs, and messenger RNAs (mRNA) expression profiles by pools of thymus tissue samples (from 9 to 11 mice) from offspring OVA-immunized or Alum-immunized mothers were analyzed via Illumina sequencing platform and bioinformatics approaches. Using a fold change >4, our results showed that seven miRNAs (mmu-miR-126a-3p, 101a-3p, 744-3p,142-5p, 15a-5p, 532-5p, and 98-5p) were differentially expressed between both groups. Ten target genes were predicted to interact with the seven selected miRNAs. There were no enriched categories of gene ontology functional annotation and pathway enrichment analysis for the target genes. Interestingly, four of the identified miRNAs (mmu-miR-15a, mmu-miR-101 mmu-miR-126, and mmu-miR-142) are related to IL-17 production. Our data is of significance because we demonstrate that maternal immunization can modulate offspring thymic maturation of IL-17-producing γδT cells possibly by an epigenetic mechanism mediated by miRNAs.


Assuntos
Hipersensibilidade/etiologia , Imunização , Linfócitos Intraepiteliais , Exposição Materna , Timo/imunologia , Animais , Feminino , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo
8.
Front Immunol ; 12: 669893, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140950

RESUMO

Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased ß-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.


Assuntos
Proliferação de Células , Senescência Celular , Síndrome de Down/metabolismo , Células Epiteliais/metabolismo , Imunossenescência , Estresse Oxidativo , Timócitos/metabolismo , Timo/metabolismo , Fatores Etários , Estudos de Casos e Controles , Proliferação de Células/genética , Senescência Celular/genética , Criança , Pré-Escolar , Síndrome de Down/genética , Síndrome de Down/imunologia , Síndrome de Down/patologia , Epigênese Genética , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunossenescência/genética , Lactente , Masculino , Estresse Oxidativo/genética , Timócitos/imunologia , Timócitos/patologia , Timo/imunologia , Timo/patologia , Transcriptoma
9.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34086055

RESUMO

T reg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of T reg lineage-specifying factor Foxp3. Foxp3 enhancers are known as distinct readers of environmental cues controlling T reg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby T reg cell suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize T reg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers leads to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable T reg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and cell-extrinsic cues in determining T reg cell suppressive capacity.


Assuntos
Elementos Facilitadores Genéticos/genética , Fatores de Transcrição Forkhead/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Sistemas CRISPR-Cas/genética , Linhagem da Célula , Epigênese Genética , Epistasia Genética , Feminino , Fatores de Transcrição Forkhead/genética , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/imunologia
10.
Folia Histochem Cytobiol ; 59(2): 75-85, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097299

RESUMO

INTRODUCTION: Regulatory T cells (Tregs) are a unique CD4+ T cell subset involved in the regulation of immune responses. The traditional immunophenotype used to define Tregs includes CD4+CD25high and the expression of the transcription factor Forkhead box protein 3 (FoxP3). A complex technique of intracellular staining, transient upregulation of FoxP3 in activated conventional T lymphocytes (Tcons), and the omission of naïve CD45RA+ Tregs with downregulated FoxP3 activity but a demethylated FOXP3 promoter region may lead to inaccurate quantification. In an attempt to meet the need for a reliable and simplified enumeration strategy, we investigated different membrane markers to capture the entire Treg compartment and to identify subpopulations of Tregs. MATERIAL AND METHODS: Analyses were performed on whole blood. Tested gating strategies were based on the expression of the following membrane antigens: CD45, CD3, CD4, CD25, CD127, CD26, CD6, CD39, CD71, HLA-DR, CD45RA and CD31. Double controls with FoxP3 were performed. RESULTS: The final enumeration panel consisted of the membrane markers CD45, CD3, CD4, CD25, CD127, CD26, CD39, CD45RA and CD31. A deep analysis of T cells with the CD4+CD25+CD127low/-CD26low/-CD45RAimmunophenotype revealed high expression of FoxP3 and/or CD39, while cells with the naïve immunophenotype, CD4+CD25+CD127low/-CD26low/-CD45RA+, presented lower expression of suppressor markers. Antigen CD31 is considered to be a valuable membrane marker of thymus-derived Tregs. CONCLUSIONS: The presented 9-color panel that can be easily applied in laboratories enables reliable enumeration of Tregs with additional information about the functionality, maturity and origin of T regulatory cells.


Assuntos
Antígenos CD/sangue , Antígenos HLA-DR/sangue , Linfócitos T Reguladores/química , Biomarcadores/sangue , Contagem de Linfócito CD4/métodos , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/sangue , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/imunologia , Humanos , Linfócitos T Reguladores/classificação , Timo/imunologia
11.
Res Vet Sci ; 138: 90-99, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34126450

RESUMO

With the rapid development of the poultry breeding industry and highly intensive production management, the losses caused by stress responses are becoming increasingly serious. To screen candidate genes related to chicken stress and provide a basis for future research on the molecular mechanisms governing the effects of stress on chicken immune function, we successfully constructed a chicken stress model by exogenously introducing corticosterone (CORT). RNA-seq technology was used to identify and analyze the mRNA and enrichment pathways of the thymus in the stress model group and the control group. The results showed that there were 101 significantly differentially expressed genes (SDEGs) (Padj < 0.05, |log2fold changes| ≥ 1 and FPKM >1), of which 44 were upregulated genes, while 57 were downregulated genes. Gene Ontology (GO) enrichment analysis found that the terms related to immunity or stress mainly included antigen processing and presentation, positive regulation of T cell-mediated immunity, and immune effector process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the main pathways related to immunity or stress were the PPAR signaling pathway, NOD-like receptor signaling pathway, and intestinal immune network for IgA production. Among the SDEGs, XCL1, HSPA8, DMB1 and BAG3 are strongly related to immunity or stress and may be important genes involved in regulating stress affecting the immune function of chickens. The above results provide a theoretical reference for subsequent research on the molecular regulatory mechanisms by which stress affects the immune function of poultry.


Assuntos
Galinhas/genética , Imunidade/genética , Timo/imunologia , Transcriptoma , Animais , Galinhas/imunologia , Distribuição Aleatória , Estresse Fisiológico/imunologia , Timo/metabolismo
12.
Eur J Immunol ; 51(9): 2345-2347, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34180542

RESUMO

The monoclonal antibody ER-TR7 was used in a great number of studies for detecting reticular fibroblasts and the ECM of lymphoid and non-lymphoid organs even if the protein recognized by the ER-TR7 antibody was not known. We have now identified native collagen VI microfibrils as its tissue antigen.


Assuntos
Anticorpos Monoclonais/imunologia , Colágeno Tipo VI/imunologia , Células Estromais/imunologia , Animais , Antígenos/imunologia , Camundongos , Baço/citologia , Baço/imunologia , Timo/citologia , Timo/imunologia
13.
Front Immunol ; 12: 676236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968086

RESUMO

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.


Assuntos
Envelhecimento/imunologia , Tolerância Central , Timo/imunologia , Fatores Etários , Células Apresentadoras de Antígenos/imunologia , Células Epiteliais/imunologia , Humanos , Linfócitos T Reguladores/imunologia
14.
Front Immunol ; 12: 671743, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046040

RESUMO

Virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains, such as the Lena strain, have demonstrated a higher thymus tropism than low virulent strains. Virulent PRRSV strains lead to severe thymus atrophy, which could be related to marked immune dysregulation. Impairment of T-cell functions through immune checkpoints has been postulated as a strategy executed by PRRSV to subvert the immune response, however, its role in the thymus, a primary lymphoid organ, has not been studied yet. Therefore, the goal of this study was to evaluate the expression of selected immune checkpoints (PD1/PDL1, CTLA4, TIM3, LAG3, CD200R1 and IDO1) in the thymus of piglets infected with two different PRRSV-1 strains. Thymus samples from piglets infected with the low virulent 3249 strain, the virulent Lena strain and mock-infected were collected at 1, 3, 6, 8 and 13 days post-infection (dpi) to analyze PRRSV viral load, relative quantification and immunohistochemical staining of immune checkpoints. PD1/PDL1, CTLA4, TIM3, LAG3 and IDO1 immune checkpoints were significantly up-regulated in the thymus of PRRSV infected piglets, especially in those infected with the virulent Lena strain from 6 dpi onwards. This up-regulation was associated with disease progression, high viral load and cell death. Co-expression of these molecules can affect T-cell development, maturation and selection, negatively regulating the host immune response against PRRSV.


Assuntos
Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Timo/imunologia , Timo/virologia , Animais , Síndrome Respiratória e Reprodutiva Suína/virologia , Suínos , Regulação para Cima , Virulência
15.
Nature ; 594(7863): 413-417, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33981034

RESUMO

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3-5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.


Assuntos
Células Dendríticas/imunologia , Microbioma Gastrointestinal/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Timo/imunologia , Envelhecimento/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , DNA Bacteriano/análise , Células Dendríticas/metabolismo , Escherichia coli/imunologia , Feminino , Masculino , Camundongos , Especificidade de Órgãos , Salmonella/imunologia , Simbiose/imunologia , Timo/metabolismo
16.
Front Immunol ; 12: 642856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054809

RESUMO

Invariant NKT (iNKT) cells are thymus-generated innate-like T cells, comprised of three distinct subsets with divergent effector functions. The molecular mechanism that drives the lineage trifurcation of immature iNKT cells into the NKT1, NKT2, and NKT17 subsets remains a controversial issue that remains to be resolved. Because cytokine receptor signaling is necessary for iNKT cell generation, cytokines are proposed to contribute to iNKT subset differentiation also. However, the precise roles and requirements of cytokines in these processes are not fully understood. Here, we show that IL-2Rß, a nonredundant component of the IL-15 receptor complex, plays a critical role in both the development and differentiation of thymic iNKT cells. While the induction of IL-2Rß expression on postselection thymocytes is necessary to drive the generation of iNKT cells, surprisingly, premature IL-2Rß expression on immature iNKT cells was detrimental to their development. Moreover, while IL-2Rß is necessary for NKT1 generation, paradoxically, we found that the increased abundance of IL-2Rß suppressed NKT1 generation without affecting NKT2 and NKT17 cell differentiation. Thus, the timing and abundance of IL-2Rß expression control iNKT lineage fate and development, thereby establishing cytokine receptor expression as a critical regulator of thymic iNKT cell differentiation.


Assuntos
Subunidade beta de Receptor de Interleucina-2/fisiologia , Células T Matadoras Naturais/fisiologia , Timo/imunologia , Animais , Diferenciação Celular , Interleucina-15/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/classificação , Células T Matadoras Naturais/citologia , Fator de Transcrição STAT5/fisiologia
17.
Diabetes ; 70(8): 1729-1737, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34035042

RESUMO

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen specificity of Treg plays an important role in their in vivo activity. We therefore assessed the diversity of the T-cell receptors (TCRs) for antigen expressed by Treg newly developed in the thymus of autoimmune type 1 diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that use of the TCRα and TCRß variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRα and TCRß chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type 1 diabetes in the NOD mouse.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Reguladores/patologia , Timo/patologia , Animais , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Timo/imunologia
18.
Front Immunol ; 12: 640595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936055

RESUMO

Treating premature infants with high oxygen is a routine intervention in the context of neonatal intensive care. Unfortunately, the increase in survival rates is associated with various detrimental sequalae of hyperoxia exposure, most notably bronchopulmonary dysplasia (BPD), a disease of disrupted lung development. The effects of high oxygen exposure on other developing organs of the infant, as well as the possible impact such disrupted development may have on later life remain poorly understood. Using a neonatal mouse model to investigate the effects of hyperoxia on the immature immune system we observed a dramatic involution of the thymic medulla, and this lesion was associated with disrupted FoxP3+ regulatory T cell generation and T cell autoreactivity. Significantly, administration of mesenchymal stromal cell-derived extracellular vesicles (MEx) restored thymic medullary architecture and physiological thymocyte profiles. Using single cell transcriptomics, we further demonstrated preferential impact of MEx treatment on the thymic medullary antigen presentation axis, as evidenced by enrichment of antigen presentation and antioxidative-stress related genes in dendritic cells (DCs) and medullary epithelial cells (mTECs). Our study demonstrates that MEx treatment represents a promising restorative therapeutic approach for oxygen-induced thymic injury, thus promoting normal development of both central tolerance and adaptive immunity.


Assuntos
Vesículas Extracelulares/transplante , Hiperóxia/complicações , Células-Tronco Mesenquimais/metabolismo , Linfócitos T , Timo , Animais , Animais Recém-Nascidos , Vesículas Extracelulares/metabolismo , Xenoenxertos , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/patologia , Timo/imunologia , Timo/patologia , Cordão Umbilical
19.
J Allergy Clin Immunol ; 147(5): 1549-1560, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33965092

RESUMO

Innate lymphoid cells (ILCs) mainly reside at barrier surfaces and regulate tissue homeostasis and immunity. ILCs are divided into 3 groups, group 1 ILCs, group 2 ILCs, and group 3 ILC3, on the basis of their similar effector programs to T cells. The development of ILCs from lymphoid progenitors in adult mouse bone marrow has been studied in detail, and multiple ILC progenitors have been characterized. ILCs are mostly tissue-resident cells that develop in the perinatal period. More recently, ILC progenitors have also been identified in peripheral tissues. In this review, we discuss the stepwise transcription factor-directed differentiation of mouse ILC progenitors into mature ILCs, the critical time windows in ILC development, and the contribution of bone marrow versus tissue ILC progenitors to the pool of mature ILCs in tissues.


Assuntos
Linfócitos/citologia , Linfócitos/imunologia , Animais , Subunidades alfa de Fatores de Ligação ao Core/imunologia , Citocinas/imunologia , Epigênese Genética , Humanos , Imunidade Inata , Infecções/imunologia , Inflamação/imunologia , Timo/imunologia , Fatores de Transcrição/imunologia
20.
Eur J Immunol ; 51(8): 2006-2026, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33960413

RESUMO

The NF-κB transcription factor c-Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c-Rel-deficient (cRel-/- ) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR signaling strength. However, these parameters are altered in the thymic Treg-precursor population, which is also markedly diminished in cRel-/- mice. Moreover, c-Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signaling, and separately in the periphery, cell cycle progression. Last, the immune suppressive function of peripheral cRel-/- tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c-Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation, and function via distinct mechanisms.


Assuntos
Proteínas Proto-Oncogênicas c-rel/imunologia , Proteínas Proto-Oncogênicas c-rel/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Timo/imunologia , Timo/metabolismo
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