Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.169
Filtrar
1.
Nat Commun ; 12(1): 5303, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489451

RESUMO

Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide-MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.


Assuntos
Antígenos Ly/genética , Linfócitos T CD8-Positivos/imunologia , Homeostase/genética , Memória Imunológica/genética , Interferon-alfa/genética , Interferon gama/genética , Febre do Nilo Ocidental/genética , Animais , Antígenos Ly/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Antígenos CD5/genética , Antígenos CD5/imunologia , Antígenos CD8/genética , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homeostase/imunologia , Interferon-alfa/imunologia , Interferon gama/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/patogenicidade
2.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426690

RESUMO

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Fatores de Transcrição Forkhead/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Homeostase/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Resposta Inflamatória Sistêmica/patologia
3.
Nat Commun ; 12(1): 4907, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389726

RESUMO

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Homeostase/imunologia , Mucosa Intestinal/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Homeostase/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
4.
Nat Commun ; 12(1): 4462, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294718

RESUMO

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Intestino Delgado/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Homeostase/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Organoides , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Subpopulações de Linfócitos T/citologia , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo
5.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34313294

RESUMO

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which started in late 2019, has caused huge social and economic losses. A growing number of investigators are focusing on understanding the interaction of SARS-CoV-2 with host cellular processes to find therapeutic approaches. New data suggest that lipid metabolism may play a significant role in regulating the response of immune cells like macrophages to viral infection, thereby affecting the outcome of the disease. Therefore, understanding the role of lipid metabolism could help develop new therapeutic approaches to mitigate the social and economic cost of coronavirus disease 2019 (COVID-19).


Assuntos
COVID-19/imunologia , COVID-19/metabolismo , Metabolismo dos Lipídeos/imunologia , Lipidômica , SARS-CoV-2/química , COVID-19/epidemiologia , Homeostase/imunologia , Humanos , Pandemias
6.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207900

RESUMO

Cytokines play a huge role in many biological processes. Their production, release and interactions are subject to a very complex mechanism. Cytokines are produced by all types of cells, they function very differently and they are characterized by synergism in action, antagonism, and aggregation activity, opposing action of one cytokine, overlapping activity, induction of another cytokine, inhibition of cytokine synthesis at the mRNA level as well as autoregulation-stimulation or inhibition of own production. The predominance of pro-inflammatory cytokines leads to a systemic inflammatory response, and anti-inflammatory-to an anti-inflammatory response. They regulate the organism's immune response and protect it against sudden disturbances in homeostasis. The synthesis and activity of cytokines are influenced by the central nervous system through the endocrine system (pituitary gland, adrenal glands).


Assuntos
Citocinas , Leite Humano , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Homeostase/imunologia , Humanos , Leite Humano/imunologia , Leite Humano/metabolismo , Hipófise/imunologia , Hipófise/metabolismo
7.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198897

RESUMO

The introduction of metallic nanoparticles (mNPs) into the diet is a matter of concern for human health. In particular, their effect on the gastrointestinal tract may potentially lead to the increased passage of gluten peptides and the activation of the immune response. In consequence, dietary mNPs could play a role in the increasing worldwide celiac disease (CeD) incidence. We evaluated the potential synergistic effects that peptic-tryptic-digested gliadin (PT) and the most-used food mNPs may induce on the intestinal mucosa. PT interaction with mNPs and their consequent aggregation was detected by transmission electron microscopy (TEM) analyses and UV-Vis spectra. In vitro experiments on Caco-2 cells proved the synergistic cytotoxic effect of PT and mNPs, as well as alterations in the monolayer integrity and tight junction proteins. Exposure of duodenal biopsies to gliadin plus mNPs triggered cytokine production, but only in CeD biopsies. These results suggest that mNPs used in the food sector may alter intestinal homeostasis, thus representing an additional environmental risk factor for the development of CeD.


Assuntos
Doença Celíaca/dietoterapia , Dieta , Glutens/metabolismo , Nanopartículas/uso terapêutico , Biópsia , Células CACO-2 , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Homeostase/imunologia , Humanos , Imunidade/efeitos dos fármacos , Imunidade/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Nanopartículas/metabolismo , Triticum/efeitos adversos
8.
Immunity ; 54(6): 1123-1136.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107271

RESUMO

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.


Assuntos
Apoptose/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Lisofosfolipídeos/imunologia , Neutrófilos/imunologia , Receptores de Lisofosfolipídeos/imunologia , Animais , Células Cultivadas , Colite/imunologia , Colo/imunologia , Homeostase/imunologia , Humanos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/imunologia
9.
Front Immunol ; 12: 662048, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084166

RESUMO

Background: Within the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development. This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio. This imbalance negatively impacts hematopoiesis, particularly in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown. Methods: We studied the role of host radio-resistant cell-derived CD40 in restoring Teff/Treg homeostasis and proper B-cell development in a murine model of BMT. We characterized the host cellular source of CD40 and performed radiation chimera analyses by transplanting WT or Cd40-KO with WT BM in the presence of T-reg and co-infusing WT or - Cd40-KO BM-MSCs. Residual host and donor T cell expansion and activation (cytokine production) and also the expression of Treg fitness markers and conversion to Th17 were analyzed. The presence of Cd40+ BM-MSCs was analyzed in a human setting in correlation with the frequency of B-cell precursors in patients who underwent HSCT and variably developed acute graft-versus-host (aGVDH) disease. Results: CD40 expression is nearly undetectable in the BM, yet a Cd40-KO recipient of WT donor chimera exhibited impaired B-cell lymphopoiesis and Treg development. Lethal irradiation promotes CD40 and OX40L expression in radio-resistant BM-MSCs through the induction of pro-inflammatory cytokines. OX40L favors Teff expansion and activation at the expense of Tregs; however, the expression of CD40 dampens OX40L expression and restores Treg homeostasis, thus facilitating proper B-cell development. Indeed, in contrast to dendritic cells in secondary lymphoid organs that require CD40 triggers to express OX40L, BM-MSCs require CD40 to inhibit OX40L expression. Conclusions: CD40+ BM-MSCs are immune regulatory elements within BM. Loss of CD40 results in uncontrolled T cell activation due to a reduced number of Tregs, and B-cell development is consequently impaired. GVHD provides an example of how a loss of CD40+ BM-MSCs and a reduction in B-cell precursors may occur in a human setting.


Assuntos
Transplante de Medula Óssea , Medula Óssea/imunologia , Antígenos CD40/genética , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , Células-Tronco Mesenquimais/imunologia , Ligante OX40/genética , Estresse Fisiológico/imunologia , Adulto , Idoso , Animais , Medula Óssea/fisiologia , Células da Medula Óssea/imunologia , Antígenos CD40/imunologia , Feminino , Homeostase/genética , Humanos , Ativação Linfocitária/imunologia , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos , Pessoa de Meia-Idade , Ligante OX40/imunologia , Linfócitos T Reguladores/imunologia , Condicionamento Pré-Transplante , Adulto Jovem
10.
Front Immunol ; 12: 666344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108967

RESUMO

Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.


Assuntos
Tecido Adiposo/imunologia , Vesículas Extracelulares/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/imunologia , Tecido Adiposo/citologia , Comunicação Celular , Humanos , Macrófagos/citologia , Obesidade/patologia , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/imunologia
11.
Eur J Immunol ; 51(8): 1980-1991, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34060652

RESUMO

High mobility group box-1 protein (HMGB1) is an alarmin that, once released, promotes inflammatory responses, alone and as a complex with the chemokine CXCL12. Here, we report that the HMGB1-CXCL12 complex plays an essential role also in homeostasis by controlling the migration of B lymphocytes. We show that extracellular HMGB1 is critical for the CXCL12-dependent egress of B cells from the Peyer's patches (PP). This promigratory function of the complex was restricted to the PPs, since HMGB1 was not required for B-cell migratory processes in other locations. Accordingly, we detected higher constitutive levels of the HMGB1-CXCL12 complex in PPs than in other lymphoid organs. HMGB1-CXCL12 in vivo inhibition was associated with a reduced basal IgA production in the gut. Collectively, our results demonstrate a role for the HMGB1-CXCL12 complex in orchestrating B-cell trafficking in homeostasis, and provide a novel target to control lymphocyte migration in mucosal immunity.


Assuntos
Linfócitos B/metabolismo , Quimiocina CXCL12/metabolismo , Proteína HMGB1/metabolismo , Imunidade nas Mucosas/imunologia , Nódulos Linfáticos Agregados/metabolismo , Animais , Linfócitos B/imunologia , Quimiocina CXCL12/imunologia , Quimiotaxia de Leucócito/imunologia , Proteína HMGB1/imunologia , Homeostase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nódulos Linfáticos Agregados/imunologia
12.
J Biomed Sci ; 28(1): 41, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34082769

RESUMO

Lysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment. In this review, we discuss the role of LSD1 in several aspects of cancer, such as hypoxia, epithelial-to-mesenchymal transition, stemness versus differentiation of cancer stem cells, as well as anti-tumor immunity. Additionally, the current understanding of the involvement of LSD1 in various other pathological processes is discussed.


Assuntos
Histona Desmetilases/genética , Homeostase/genética , Neoplasias/genética , Animais , Diferenciação Celular/genética , Transição Epitelial-Mesenquimal/genética , Histona Desmetilases/imunologia , Histona Desmetilases/metabolismo , Homeostase/imunologia , Humanos , Hipóxia/enzimologia , Hipóxia/genética , Hipóxia/imunologia , Camundongos , Neoplasias/enzimologia , Neoplasias/imunologia , Células-Tronco Neoplásicas/fisiologia , Evasão Tumoral/genética
13.
FEBS Lett ; 595(14): 1962-1974, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080184

RESUMO

Regulatory T cells (Tregs) are indispensable for the maintenance of immunological self-tolerance and homeostasis. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is required for optimal Treg induction. Here, we reveal that human-induced Tregs (iTregs) lacking hnRNPA1 show reduced expression of the transcription factor FOXP3, increased ubiquitination level of FOXP3, and impaired suppressive abilities. Human naïve CD4 T cells with hnRNPA1 knockdown show a decreased Treg differentiation ratio. hnRNPA1 could interact with FOXP3 as well as with the E3 ligase Stub1. The phosphorylation at hnRNPA1 S199 could increase both interactions. The overexpression of FOXP3 in Tregs containing shhnRNPA1 could not recover the phenotype caused by hnRNPA1 knockdown. Therefore, there might be multiple essential pathways regulated by hnRNPA1 in Tregs. In conclusion, we present a new role of hnRNPA1 in promoting Treg function, indicating it as a promising target for tumor therapies.


Assuntos
Fatores de Transcrição Forkhead/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Ubiquitina-Proteína Ligases/genética , Diferenciação Celular , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Células HEK293 , Ribonucleoproteína Nuclear Heterogênea A1/antagonistas & inibidores , Ribonucleoproteína Nuclear Heterogênea A1/imunologia , Homeostase/imunologia , Humanos , Fosforilação , Cultura Primária de Células , Ligação Proteica , Estabilidade Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Tolerância a Antígenos Próprios/genética , Transdução de Sinais , Linfócitos T Citotóxicos/citologia , Linfócitos T Reguladores/citologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação
14.
J Immunol ; 206(10): 2251-2263, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965905

RESUMO

The laboratory rat continues to be the model of choice for many studies of physiology, behavior, and complex human diseases. Cells of the mononuclear phagocyte system (MPS; monocytes, macrophages, and dendritic cells) are abundant residents in every tissue in the body and regulate postnatal development, homeostasis, and innate and acquired immunity. Recruitment and proliferation of MPS cells is an essential component of both initiation and resolution of inflammation. The large majority of current knowledge of MPS biology is derived from studies of inbred mice, but advances in technology and resources have eliminated many of the advantages of the mouse as a model. In this article, we review the tools available and the current state of knowledge of development, homeostasis, regulation, and diversity within the MPS of the rat.


Assuntos
Imunidade Adaptativa , Modelos Animais de Doenças , Imunidade Inata , Sistema Fagocitário Mononuclear/imunologia , Ratos , Animais , Genoma , Homeostase/imunologia , Inflamação/imunologia , Fator Estimulador de Colônias de Macrófagos/genética , Camundongos , Mutação , Fenótipo
15.
Front Immunol ; 12: 671579, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981317

RESUMO

The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cells in vitro for clinical application, and summarize the recent progress of Tr1 cells in transplantation.


Assuntos
Homeostase/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes/imunologia , Humanos
16.
Eur J Immunol ; 51(7): 1592-1601, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34010475

RESUMO

The adaptive immune system has the important ability to generate and maintain a memory for antigens once encountered. Recent progress in understanding the organization of immunological memory has challenged the established paradigm of maintenance of memory by restless, circulating, and "homeostatically" proliferating lymphocytes. Among other tissues, the bone marrow has emerged as a preferred resting place for memory lymphocytes providing both local and systemic long-term protection. Why the bone marrow? There, mesenchymal stromal cells provide a privileged environment for quiescent memory B and T lymphocytes, the protagonists of secondary immune reactions, and for memory plasma cells providing persistent humoral immunity. In this review, we discuss the dedicated role of the bone marrow for the maintenance of memory lymphocytes and its implications for immunological memory.


Assuntos
Medula Óssea/imunologia , Memória Imunológica/imunologia , Imunidade Adaptativa/imunologia , Animais , Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Homeostase/imunologia , Humanos , Plasmócitos/imunologia , Linfócitos T/imunologia
17.
Nature ; 594(7861): 100-105, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33981041

RESUMO

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.


Assuntos
Envelhecimento/imunologia , Envelhecimento/fisiologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Imunossenescência/imunologia , Imunossenescência/fisiologia , Especificidade de Órgãos/imunologia , Especificidade de Órgãos/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Dano ao DNA/imunologia , Dano ao DNA/fisiologia , Reparo do DNA/imunologia , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/fisiologia , Homeostase/imunologia , Homeostase/fisiologia , Sistema Imunitário/efeitos dos fármacos , Imunossenescência/efeitos dos fármacos , Masculino , Camundongos , Especificidade de Órgãos/efeitos dos fármacos , Rejuvenescimento , Sirolimo/farmacologia , Baço/citologia , Baço/transplante
18.
J Leukoc Biol ; 110(2): 271-281, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974295

RESUMO

Recent accumulating evidence supports the hypothesis that the intricate interaction between gut microbiota and the immune system profoundly affects health and disease in humans and mice. In this context, microbiota plays an important role in educating and shaping the host immune system which, in turn, regulates gut microbiota diversity and function to maintain homeostasis. Studies have demonstrated that intestinal microbiota participates in shaping B cells in health and disease settings. Herein, we review the recent progress in understanding how microbiota regulates B-cell development, focusing on early-life B-cell repertoire generation in GALT and how microbial products, including microbial antigens and metabolites, affect B-cell activation and differentiation to ultimately regulate B-cell function. We also discuss the interaction between gut microbiota and B cells under pathogenic conditions and highlight new approaches that can be applied to treat various diseases.


Assuntos
Linfócitos B/imunologia , Suscetibilidade a Doenças , Microbioma Gastrointestinal/imunologia , Homeostase , Animais , Linfócitos B/metabolismo , Suscetibilidade a Doenças/imunologia , Disbiose/imunologia , Homeostase/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia
19.
Nat Cell Biol ; 23(5): 476-484, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958758

RESUMO

Organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remains elusive. The skin epidermis comprises mostly epithelial cells, but also harbours Langerhans cells (LCs) and dendritic epidermal T cells (DETCs). Whether and how distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, by tracking individual cells in the skin of live adult mice over time, we show that LCs and DETCs actively maintain a non-random spatial distribution despite continuous turnover of neighbouring basal epithelial cells. Moreover, the density of epithelial cells regulates the composition of LCs and DETCs in the epidermis. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.


Assuntos
Células Epidérmicas/citologia , Epiderme/metabolismo , Pele/citologia , Linfócitos T/imunologia , Animais , Células Epidérmicas/imunologia , Epiderme/imunologia , Homeostase/imunologia , Homeostase/fisiologia , Junções Intercelulares/patologia , Camundongos Transgênicos , Pele/imunologia
20.
Immunity ; 54(7): 1543-1560.e6, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34004141

RESUMO

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.


Assuntos
Sistema y+ de Transporte de Aminoácidos/imunologia , Proliferação de Células/fisiologia , Linfócitos T Reguladores/imunologia , Adulto , Autoimunidade/imunologia , Células Cultivadas , Feminino , Homeostase/imunologia , Humanos , Tolerância Imunológica/imunologia , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Fator 2 Relacionado a NF-E2/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...