RESUMO
Cysteine cathepsins are primarily involved in the degradation and recycling of proteins in endo-lysosomal compartments but are also gaining recognition as pivotal proteolytic contributors to various immune functions. Through their extracellular proteolytic activities within the hematopoietic stem cell niche, they are involved in progenitor cell mobilization and differentiation. Cysteine cathepsins, such as cathepsins L and S contribute to antigen-induced adaptive immunity through major histocompatibility complex class II antigen presentation whereas cathepsin X regulates T-cell migration. By regulating toll-like receptor signaling and cytokine secretion cysteine cathepsins activate innate immune cells and affect their functional differentiation. Cathepsins C and H are expressed in cytotoxic T lymphocytes and natural killer cells and are involved in processing of pro-granzymes into proteolytically active forms. Cytoplasmic activities of cathepsins B and L contribute to the maintenance of homeostasis of the adaptive immune response by regulating cell death of T and B lymphocytes. The expression pattern, localization, and activity of cysteine cathepsins is tightly connected to their function in immune cells. Furthermore, cysteine cathepsins together with their endogenous inhibitors, serve as mediators in the interplay between cancer and immune cells that results in immune cell anergy. The aim of the present article is to review the mechanisms of dysregulation of cysteine cathepsins and their inhibitors in relation to immune dysfunction to address new possibilities for regulation of their function.
Assuntos
Diferenciação Celular/imunologia , Cisteína Proteases/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Imunomodulação , Animais , Diferenciação Celular/genética , Anergia Clonal/imunologia , Cisteína Proteases/química , Cisteína Proteases/genética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Tolerância Imunológica , Imunomodulação/efeitos dos fármacos , Imunossenescência/efeitos dos fármacos , Família Multigênica , Organogênese/genética , Organogênese/imunologia , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The thymus plays a key role in adaptive immunity by generating a diverse population of T cells that defend the body against pathogens. Various factors from disease and toxic insults contribute to the degeneration of the thymus resulting in a fewer output of T cells. Consequently, the body is prone to a wide host of diseases and infections. In this review, first, the relevance of the thymus is discussed, followed by thymic embryological organogenesis and anatomy as well as the development and functionality of T cells. Attempts to regenerate the thymus include in vitro methods, such as forming thymic organoids aided by biofabrication techniques that are transplantable. Ex vivo methods that have shown promise in enhancing thymic regeneration are also discussed. Current regenerative technologies have not yet matched the complexity and functionality of the thymus. Therefore, emerging techniques that have shown promise and the challenges that lie ahead are explored.
Assuntos
Organogênese/imunologia , Organogênese/fisiologia , Regeneração/fisiologia , Timo/imunologia , Timo/fisiologia , Humanos , Regeneração/imunologia , Rejuvenescimento/fisiologia , Linfócitos T/imunologia , Linfócitos T/fisiologiaRESUMO
The sympathetic nervous system is composed of an endocrine arm, regulating blood adrenaline and noradrenaline, and a local arm, a network of fibers innervating immune organs. Here, we investigated the impact of the local arm of the SNS in an inflammatory response in the colon. Intra-rectal insertion of an optogenetic probe in mice engineered to express channelrhodopsin-2 in tyrosine hydroxylase cells activated colonic sympathetic fibers. In contrast to systemic application of noradrenaline, local activation of sympathetic fibers attenuated experimental colitis and reduced immune cell abundance. Gene expression profiling showed decreased endothelial expression of the adhesion molecule MAdCAM-1 upon optogenetic stimulation; this decrease was sensitive to adrenergic blockers and 6-hydroxydopamine. Antibody blockade of MAdCAM-1 abrogated the optogenetic effect on immune cell extravasation into the colon and the pathology. Thus, sympathetic fibers control colonic inflammation by regulating immune cell extravasation from circulation, a mechanism likely relevant in multiple organs.
Assuntos
Colite/imunologia , Colo/imunologia , Colo/inervação , Organogênese/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/métodosRESUMO
The female sex steroid 17ß-oestradiol (E2) is involved in the regulation of numerous physiological functions, including the immune system development and performance. The role of oestrogens during ontogenesis is, however, not well studied. In rodents and fish, thymus maturation appears to be oestrogen-dependent. Nevertheless, little is known about the function of oestrogen in immune system development. To further the understanding of the role of oestrogens in fish immune system ontogenesis, fingerlings of European sea bass (Dicentrarchus labrax) were exposed for 30 days to 20 ng E2·L-1, at two ages tightly related to thymic maturation, i.e., 60 or 90 days post hatch (dph). The expression of nuclear and membrane oestrogen receptors was measured in the thymus and spleen, and the expression of several T cell-related gene markers was studied in both immune organs, as well as in the liver. Waterborne E2-exposure at 20.2 ± 2.1 (S.E.) ng·L-1 was confirmed by radioimmunoassay, leading to significantly higher E2-contents in the liver of exposed fish. The majority of gene markers presented age-dependent dynamics in at least one of the organs, confirming thymus maturation, but also suggesting a critical ontogenetic window for the implementation of liver resident γδ and αß T cells. The oestrogen receptors, however, remained unchanged over the age and treatment comparisons with the exception of esr2b, which was modulated by E2 in the younger cohort and increased its expression with age in the thymus of the older cohort, as did the membrane oestrogen receptor gpera. These results confirm that oestrogen-signalling is involved in thymus maturation in European sea bass, as it is in mammals. This suggests that esr2b and gpera play key roles during thymus ontogenesis, particularly during medulla maturation. In contrast, the spleen expressed low or non-detectable levels of oestrogen receptors. The E2-exposure decreased the expression of tcrγ in the liver in the cohort exposed from 93 to 122 dph, but not the expression of any other immune-related gene analysed. These results indicate that the proliferation/migration of these innate-like T cell populations is oestrogen-sensitive. In regard to the apparent prominent role of oestrogen-signalling in the late thymus maturation stage, the thymic differentiation of the corresponding subpopulations of T cells might be regulated by oestrogen. To the best of our knowledge, this is the first study investigating the dynamics of both nuclear and membrane oestrogen receptors in specific immune organs in a teleost fish at very early stages of immune system development as well as to examine thymic function in sea bass after an exposure to E2 during ontogenesis.
Assuntos
Bass/imunologia , Estradiol/metabolismo , Proteínas de Peixes/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Bass/crescimento & desenvolvimento , Bass/metabolismo , Feminino , Tolerância Imunológica , Fígado/crescimento & desenvolvimento , Fígado/imunologia , Linfopoese/imunologia , Masculino , Organogênese/imunologia , Timo/crescimento & desenvolvimento , Timo/imunologiaRESUMO
STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4ß7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.
Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfonodos/imunologia , Linfócitos/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Mutação com Ganho de Função/imunologia , Tecido Linfoide/imunologia , Camundongos , Organogênese/imunologiaRESUMO
BACKGROUND & AIMS: Organ-level research using an animal model lacking Il2rg, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable and would be a powerful tool to gain deeper insights into the symptoms of patients with X-SCID. METHODS: We used an X-SCID animal model, which was first established in our group by the deletion of Il2rg gene in pigs, to understand the clinical signs from multiple perspectives based on pathology, immunology, microbiology, and nutrition. We also treated the X-SCID pigs with bone marrow transplantation (BMT) for mimicking a current therapeutic treatment for patients with X-SCID and investigated the effect at the organ-level. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID. RESULTS: We demonstrated that X-SCID pigs completely lacked Peyer's patches (PPs) and IgA production in the small intestine, but possessed some dysfunctional intestinal T and B cells. Another novel discovery was that X-SCID pigs developed a heterogeneous intestinal microflora and possessed abnormal plasma metabolites, indicating that X-SCID could be an immune disorder that affects various in vivo functions. Importantly, the organogenesis of PPs in X-SCID pigs was not promoted by BMT. Although a few isolated lymphoid follicles developed in the small intestine of BMT-treated X-SCID pigs, there was no evidence that they contributed to IgA production and microflora formation. Consistently, most patients with X-SCID who received BMT possessed abnormal intestinal immune and microbial environments regardless of the presence of sufficient serum IgG. CONCLUSIONS: These results indicate that the current BMT therapies for patients with X-SCID may be insufficient to induce the organogenesis of intestinal lymphoid tissues that are associated with numerous functions in vivo.
Assuntos
Transplante de Medula Óssea , Subunidade gama Comum de Receptores de Interleucina/genética , Mucosa Intestinal/crescimento & desenvolvimento , Nódulos Linfáticos Agregados/crescimento & desenvolvimento , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Adolescente , Adulto , Animais , Animais Geneticamente Modificados , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/imunologia , Técnicas de Inativação de Genes , Humanos , Imunidade nas Mucosas , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Masculino , Organogênese/genética , Organogênese/imunologia , Nódulos Linfáticos Agregados/imunologia , Suínos , Resultado do Tratamento , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologiaRESUMO
The cyclin-dependent kinase 5 (CDK5) represents an unusual member of the family of cyclin-dependent kinases, which is activated upon binding to non-cyclin p35 and p39 proteins. The role of CDK5 in the nervous system has been very well established. In addition, there is growing evidence that CDK5 is also active in non-neuronal tissues, where it has been postulated to affect a variety of functions such as the immune response, angiogenesis, myogenesis, melanogenesis and regulation of insulin levels. Moreover, high levels of CDK5 have been observed in different tumour types, and CDK5 was proposed to play various roles in the tumorigenic process. In this review, we discuss these various CDK5 functions in normal physiology and disease, and highlight the therapeutic potential of targeting CDK5.
Assuntos
Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Transdução de Sinais , Animais , Humanos , Imunomodulação , Modelos Biológicos , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Organogênese/genética , Organogênese/imunologiaRESUMO
Zebrafish can efficiently regenerate complex tissue structures with a highly developed innate and adaptive immune system, which provides a model to investigate the roles of immune cells in tissue repair and regeneration. Two groups recently reported zebrafish mutants deficient in a forkhead box P3 (FOXP3) ortholog, which helped reveal the conserved immunosuppressive function of zebrafish FOXP3 in vivo. Zebrafish FOXP3 defines the development of a subset of T cell lineage with the conserved gene expression profile of mammalian regulatory T cells (Tregs). In damaged organs, zebrafish Tregs rapidly migrate to the injury site, where they promote the proliferation of regeneration precursor cells by producing tissue-specific regenerative factors through a distinct mechanism from the canonical anti-inflammatory pathway. These findings illuminate the potential for using zebrafish as an effective model in Treg research and demonstrate organ-specific roles for Tregs in maintaining proregenerative capacity that could potentially be harnessed for use in diverse regeneration therapies.
Assuntos
Organogênese/imunologia , Regeneração/imunologia , Linfócitos T Reguladores/imunologia , Peixe-Zebra/imunologia , Peixe-Zebra/fisiologia , Animais , Fatores de Transcrição Forkhead/imunologia , Proteínas de Peixe-Zebra/imunologiaRESUMO
Antibody-like biopharmaceuticals cross the placenta by utilizing existing transport pathways (e.g., FcRn receptor). There are limited data evaluating this transfer during organogenesis in any species. Understanding placental transfer of antibody-like biopharmaceuticals can help to predict risk of developmental toxicity across species, including humans. To complement previously published placental transfer data in the rat with humanized IgGΔ2 (hIgG2), the timing and magnitude of transfer in the cynomolgus monkey and embryo/fetal biodistribution of maternally administered 125 I-radiolabeled hIgG2 was quantified on gestation days (GD) 35, 40, 50, 70, and 140 using gamma counting and whole body autoradiography 24 hr following intravenous injection. Chorioallantoic placental tissues were collected at all time points for Western Blot analysis with anti-FcRn antibody. Maternally administered 125 I-hIgG2 was found in embryo/fetal tissues at all time points, including organogenesis. Embryo/fetal plasma 125 I-hIgG2 concentration increased during gestation, but only slightly up to GD 70 in embryo/fetal tissues, with hIgG2 tissue concentrations generally similar between GD70 and 140. The embryo/fetal:maternal 125 I-hIgG2 plasma concentration ratio was approximately 2.3 fold higher on GD 140, in comparison to ratios on GD 40. Importantly, placental FcRn protein expression was confirmed at all timepoints. These data demonstrate placental transfer of hIgG2 in a nonhuman primate model, and at levels comparable to the rat model, raising the potential for adverse developmental outcomes by direct antibody binding to biological targets.
Assuntos
Imunoglobulina G/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Feto/metabolismo , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/metabolismo , Radioisótopos do Iodo/metabolismo , Macaca fascicularis/imunologia , Macaca fascicularis/metabolismo , Troca Materno-Fetal/fisiologia , Organogênese/imunologia , Organogênese/fisiologia , Gravidez , Distribuição Tecidual/imunologiaRESUMO
Lymph nodes (LNs) are crucial for the orchestration of immune responses. LN reactions depend on interactions between incoming and local immune cells, and stromal cells. To mediate these cellular interactions an organized vascular network within the LN exists. In general, the LN vasculature can be divided into two components: blood vessels, which include the specialized high endothelial venules that recruit lymphocytes from the bloodstream, and lymphatic vessels. Signaling via TNF receptor (R) superfamily (SF) members has been implicated as crucial for the development and function of LNs and the LN vasculature. In recent years the role of cell-specific signaling of TNFRSF members in different endothelial cell (EC) subsets and their roles in development and maintenance of lymphoid organs has been elucidated. Here, we discuss recent insights into EC-specific TNFRSF member signaling and highlight its importance in different EC subsets in LN organogenesis and function during health, and in lymphocyte activation and tertiary lymphoid structure formation during inflammation.
Assuntos
Células Endoteliais/imunologia , Tecido Linfoide/embriologia , Tecido Linfoide/imunologia , Organogênese/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Animais , Humanos , Inflamação/imunologia , Ativação Linfocitária/imunologiaRESUMO
Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.
Assuntos
Sistema Imunitário/metabolismo , Organogênese/imunologia , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Ativação Linfocitária/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , UbiquitinaçãoRESUMO
A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar lung development is still lacking. To construct such a model, we profiled mRNA, microRNA, DNA methylation, and proteomics of developing murine alveoli isolated by laser capture microdissection at 14 predetermined time points. We developed a detailed comprehensive and interactive model that provides information about the major expression trajectories, the regulators of specific key events, and the impact of epigenetic changes. Intersecting the model with single-cell RNA-Seq data led to the identification of active pathways in multiple or individual cell types. We then constructed a similar model for human lung development by profiling time-series human omics data sets. Several key pathways and regulators are shared between the reconstructed models. We experimentally validated the activity of a number of predicted regulators, leading to new insights about the regulation of innate immunity during lung development.
Assuntos
Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Pulmão/metabolismo , Proteômica/métodos , Alvéolos Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Criança , Pré-Escolar , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade Inata/genética , Lactente , Recém-Nascido , Pulmão/crescimento & desenvolvimento , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/classificação , MicroRNAs/genética , MicroRNAs/imunologia , Organogênese/genética , Organogênese/imunologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Alvéolos Pulmonares/imunologia , RNA Mensageiro/classificação , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Análise de Célula Única , TranscriptomaRESUMO
Cellular architectural proteins often participate in organ development and maintenance. Although functional decay of some of these proteins during aging is known, the cell-type-specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin-B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An up-regulation of proinflammatory cytokines in the intra-thymic myeloid immune cells during aging accompanies a gradual reduction of lamin-B1 in adult TECs. We show that these cytokines can cause senescence and lamin-B1 reduction of the young adult TECs. Lamin-B1 supports the expression of TEC genes that can help maintain the adult TEC subtypes we identified by single-cell RNA-sequencing, thymic architecture, and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation-driven decay which can in turn contribute to age-associated organ degeneration.
Assuntos
Células Epiteliais/metabolismo , Imunossenescência/genética , Lamina Tipo B/metabolismo , Timo/crescimento & desenvolvimento , Animais , Diferenciação Celular/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Inflamação/metabolismo , Lamina Tipo B/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organogênese/genética , Organogênese/imunologia , Timo/citologia , Regulação para Cima/genéticaRESUMO
Inflammation-induced lymphangiogenesis is a widely accepted concept. However, most of the inflammatory factors and their related mechanisms have not been clarified. It has been reported that sphingosine-1-phosphate (S1P) is not only closely related to the chronic inflammatory process but also affects angiogenesis. Therefore, we investigated the inflammatory effects of S1P on human lymphatic endothelial cells (HLECs). Our results showed that S1P promotes tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) secretion in HLECs. We also confirmed that S1P-stimulated TNF-α and IL-1ß secretion is mediated through S1P receptor 1 (S1PR1). Using TNF-α siRNA and IL-1ß siRNA, we found that TNF-α and IL-1ß play essential roles in S1P-induced HLEC proliferation, migration, and tube formation. S1P induces phosphorylation of NF-κB p65 and activation of NF-κB nuclear translocation. A S1PR1 antagonist (W146) and NF-κB inhibitor (BAY11-7082) inhibited S1P-induced TNF-α and IL-1ß secretion and prevented NF-κB nuclear translocation. Taken together, the results demonstrated for the first time that S1P promotes the secretion of TNF-α and IL-1ß in HLECs via S1PR1-mediated NF-κB signaling pathways, thus affecting lymphangiogenesis. The study provides a new strategy for finding treatments for lymphangiogenesis-related diseases.
Assuntos
Células Endoteliais/fisiologia , Inflamação/imunologia , Linfangiogênese/imunologia , Organogênese/imunologia , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lisofosfolipídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação , RNA Interferente Pequeno/genética , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/imunologia , Receptores de Esfingosina-1-Fosfato , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Thymus development is critical to the adaptive immune system, yet a comprehensive transcriptional framework capturing thymus organogenesis at single-cell resolution is still needed. We applied single-cell RNA sequencing (RNA-seq) to capture 8 days of thymus development, perturbations of T cell receptor rearrangement, and in vitro organ cultures, producing profiles of 24,279 cells. We resolved transcriptional heterogeneity of developing lymphocytes, and genetic perturbation confirmed T cell identity of conventional and non-conventional lymphocytes. We characterized maturation dynamics of thymic epithelial cells in vivo, classified cell maturation state in a thymic organ culture, and revealed the intrinsic capacity of thymic epithelium to preserve transcriptional regularity despite exposure to exogenous retinoic acid. Finally, by integrating the cell atlas with human genome-wide association study (GWAS) data and autoimmune-disease-related genes, we implicated embryonic thymus-resident cells as possible participants in autoimmune disease etiologies. This resource provides a single-cell transcriptional framework for biological discovery and molecular analysis of thymus organogenesis.
Assuntos
Diferenciação Celular/imunologia , Análise de Sequência de RNA/métodos , Linfócitos T/imunologia , Timo/embriologia , Animais , Doenças Autoimunes/imunologia , Embrião de Mamíferos , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Organogênese/imunologia , Linfócitos T/citologia , Timo/citologiaRESUMO
Monocytes and macrophages are critical effectors and regulators of innate immune response. They not only play crucial and distinctive roles in homeostasis, but also contribute to some pathologic processes. The heterogeneity of the macrophage lineage has been widely recognized and, in part, is a result of the specialization of resident macrophages in particular tissue microenvironments. Monocytes are usually known to originate in the bone marrow from a common myeloid progenitor that is shared with neutrophils, and they are then released into the peripheral blood. However, the origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. During embryonic organogenesis, macrophages derived from yolk sac and fetal liver precursors are seeded throughout tissues, persisting in the adulthood as resident, self-maintaining populations. After birth, bone marrow-derived monocytes can replenish tissue resident macrophages following injury, infection and inflammation. In this review, we will mainly summarize our current understanding on the origin, ontogeny and fates of tissue macrophages and will briefly discuss the molecular regulation of resident macrophage homeostasis in physiological situation.
Assuntos
Infecções/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células da Medula Óssea/citologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Microambiente Celular/imunologia , Heterogeneidade Genética , Humanos , Imunidade Inata/genética , Infecções/genética , Infecções/patologia , Inflamação/genética , Inflamação/patologia , Fígado/crescimento & desenvolvimento , Fígado/imunologia , Macrófagos/citologia , Monócitos/citologia , Organogênese/genética , Organogênese/imunologia , Saco Vitelino/crescimento & desenvolvimento , Saco Vitelino/imunologiaRESUMO
The attenuation of ancestral pro-regenerative pathways may explain why humans do not efficiently regenerate damaged organs. Vertebrate lineages that exhibit robust regeneration, including the teleost zebrafish, provide insights into the maintenance of adult regenerative capacity. Using established models of spinal cord, heart, and retina regeneration, we discovered that zebrafish Treg-like (zTreg) cells rapidly homed to damaged organs. Conditional ablation of zTreg cells blocked organ regeneration by impairing precursor cell proliferation. In addition to modulating inflammation, infiltrating zTreg cells stimulated regeneration through interleukin-10-independent secretion of organ-specific regenerative factors (Ntf3: spinal cord; Nrg1: heart; Igf1: retina). Recombinant regeneration factors rescued the regeneration defects associated with zTreg cell depletion, whereas Foxp3a-deficient zTreg cells infiltrated damaged organs but failed to express regenerative factors. Our data delineate organ-specific roles for Treg cells in maintaining pro-regenerative capacity that could potentially be harnessed for diverse regenerative therapies.
Assuntos
Regeneração/fisiologia , Linfócitos T Reguladores/fisiologia , Peixe-Zebra/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/fisiologia , Coração/fisiologia , Modelos Animais , Regeneração Nervosa/fisiologia , Organogênese/imunologia , Organogênese/fisiologia , Retina/fisiologia , Medula Espinal/fisiologia , Proteínas de Peixe-Zebra/fisiologiaRESUMO
During αßT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3+ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin ß receptor (LTßR), we show that thymic tolerance mechanisms operate independently of LTßR-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LTßR-mediated medulla organogenesis. Moreover, we demonstrate that LTßR controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LTßR-mediated regulation of the thymic DC pool.
Assuntos
Tolerância Central/imunologia , Células Epiteliais/imunologia , Receptor beta de Linfotoxina/imunologia , Timo/imunologia , Animais , Autoantígenos/imunologia , Tolerância Central/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/metabolismo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Organogênese/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timo/embriologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
The problem of the formation of new lymphoid structures (neolymphogenesis) is quite controversial and widely discussed in the literature. Under normal conditions, lymphoid organs arise only in the process of fetal development (organogenesis), however in long-standing chronic inflammatory processes, nonhealing wounds, autoimmune diseases, oncologic pathology spontaneous formation of new lymphoid structures was noted. The structures of the peripheral lymphoid formations include the lymphocytes arranged singly and in clusters (infiltration), lymphoid nodules and lymph nodes. The morphogenesis of the components of lymphoid tissue and the possibility of creating artificial lymphoid structures, reproducing the function of the natural ones, is demonstrated. Important role in the development of lymphoid structures is played by mediators of inflammation, cytokines of the family of lymphotoxins, tumor necrosis factor. The possibilities of prosthetic substitution of the functions of the lymphoid structures are described for the activation of protective processes in the body.
Assuntos
Desenvolvimento Fetal/imunologia , Linfonodos , Linfócitos/imunologia , Linfotoxina-alfa/imunologia , Organogênese/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Humanos , Linfonodos/embriologia , Linfonodos/imunologiaRESUMO
Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue. Since the mammary gland (MG) is the only organ developing predominantly after birth, we utilized it as a powerful system to study adaptive immune regulation of organogenesis. We found that antigen-mediated interactions between mammary antigen-presenting cells and interferon-γ (IFNγ)-producing CD4+ T helper 1 cells participate in MG postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement. IFNγ then affects luminal lineage differentiation. This function of adaptive immune responses, regulating normal development, changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance and cancer transformation.