RESUMO
Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
Assuntos
Quimiocinas/metabolismo , Imunidade/fisiologia , Receptores de Quimiocinas/metabolismo , Imunidade Adaptativa/fisiologia , Animais , Movimento Celular/imunologia , Homeostase , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata/fisiologia , Memória Imunológica , Inflamação/imunologia , Inflamação/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.
Assuntos
Receptores CXCR6/metabolismo , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral , Animais , Antígeno B7-H1/metabolismo , Comunicação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Quimiocina CXCL16 , Células Dendríticas/metabolismo , Interleucina-12/metabolismo , Interleucina-15/metabolismo , Ligantes , Linfonodos/metabolismo , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos C57BLRESUMO
Regulatory T (Treg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about Treg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on Treg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2+ Treg cells and deletion of IL-1Ra in Treg cells increased granulocyte influx into the lung. Treg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by Treg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue Treg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.
Assuntos
Influenza Humana , Linfócitos T Reguladores , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/metabolismo , Linfócitos/metabolismo , Animais , CamundongosRESUMO
Foxp3+ regulatory T (Treg) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether Treg cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2+ Treg cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2+ Treg cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in Treg cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for Treg cell-mediated suppression of γδ T cells. This response resulted in fewer eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing allergen-induced inflammation. Thus, we define a fundamental role for ST2+ Treg cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.
Assuntos
Imunomodulação , Interleucina-33/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Alérgenos/imunologia , Animais , Biomarcadores , Imunofenotipagem , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , CamundongosRESUMO
CD8+ T cells responding to chronic infection adapt an altered differentiation program that provides some restraint on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8+ T cell differentiation in chronic infection has important therapeutic implications. Here, we find that the chemokine receptor CXCR3 is highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulates the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 is produced by inflammatory monocytes and fibroblasts of the splenic red pulp, where it grants stem-like cells access to signals promoting differentiation and limits their exposure to pro-survival niches in the white pulp. Consequently, functional CD8+ T cell responses are greater in Cxcl10-/- mice and are associated with a lower viral set point.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL10/metabolismo , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Monócitos/metabolismo , Receptores CXCR3/metabolismo , Baço/patologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Diferenciação Celular , Proliferação de Células , Autorrenovação Celular , Quimiocina CXCL10/genética , Doença Crônica , Seleção Clonal Mediada por Antígeno , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR3/genéticaRESUMO
Chemokines are chemotactic cytokines that regulate the migration of immune cells. Chemokines function as cues for the coordinated recruitment of immune cells into and out of tissue and also guide the spatial organization and cellular interactions of immune cells within tissues. Chemokines are critical in directing immune cell migration necessary to mount and then deliver an effective anti-tumor immune response; however, chemokines also participate in the generation and recruitment of immune cells that contribute to a pro-tumorigenic microenvironment. Here, we review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.
Assuntos
Quimiocinas/imunologia , Imunidade/imunologia , Neoplasias/imunologia , Animais , Carcinogênese/imunologia , Movimento Celular/imunologia , Humanos , Microambiente Tumoral/imunologiaRESUMO
Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8+ T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8+ T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103+ dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR3/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Humanos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4(-/-) mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, which are prone to systemic lupus erythematosus (SLE), and inhibited the antiviral immune response to influenza virus. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Receptores Imunológicos/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Autoanticorpos/metabolismo , Autoimunidade/genética , Células Cultivadas , Citocinas/metabolismo , Humanos , Imunidade Inata/genética , Mediadores da Inflamação/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , RNA Interferente Pequeno/genética , Receptores Imunológicos/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b+ DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b+ DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b+ DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169+SIGN-R1+ macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b+ DC migration. In CCR8-deficient mice, CD301b+ DCs remained in the SCS and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined a CCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169+SIGN-R1+ macrophages control the polarization of the adaptive immune response.
Assuntos
Células Dendríticas/fisiologia , Hipersensibilidade/imunologia , Linfonodos/imunologia , Receptores CCR7/metabolismo , Receptores CCR8/metabolismo , Animais , Antígenos CD/metabolismo , Movimento Celular , Células Cultivadas , Quimiocina CCL8/metabolismo , Modelos Animais de Doenças , Feminino , Cadeias alfa de Integrinas/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR8/genéticaRESUMO
Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol-25-hydroxylase+ cells located at the T-zone perimeter, Cxcl9+ TRCs in the T-zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state.
Assuntos
Linfonodos/imunologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Células Estromais/imunologia , Transcriptoma/imunologia , Animais , Quimiocina CCL19/genética , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Feminino , Linfonodos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Endogâmicos C57BL , Células Estromais/metabolismoRESUMO
A defining feature of vertebrate immunity is the acquisition of immunological memory, which confers enhanced protection against pathogens by mechanisms that are incompletely understood. Here, we compared responses by virus-specific naive T cells (T(N)) and central memory T cells (T(CM)) to viral antigen challenge in lymph nodes (LNs). In steady-state LNs, both T cell subsets localized in the deep T cell area and interacted similarly with antigen-presenting dendritic cells. However, upon entry of lymph-borne virus, only T(CM) relocalized rapidly and efficiently toward the outermost LN regions in the medullary, interfollicular, and subcapsular areas where viral infection was initially confined. This rapid peripheralization was coordinated by a cascade of cytokines and chemokines, particularly ligands for T(CM)-expressed CXCR3. Consequently, in vivo recall responses to viral infection by CXCR3-deficient T(CM) were markedly compromised, indicating that early antigen detection afforded by intranodal chemokine guidance of T(CM) is essential for efficient antiviral memory.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Quimiocina CXCL9/imunologia , Células Dendríticas/imunologia , Interferon gama/imunologia , Linfonodos/citologia , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR3/imunologia , Células Estromais/imunologia , Vírus da Estomatite Vesicular IndianaRESUMO
The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease.
Assuntos
Apoptose/genética , Apoptose/imunologia , Autoimunidade/genética , Receptores Depuradores Classe F/genética , Receptores Depuradores Classe F/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Complemento C1q/química , Complemento C1q/imunologia , Complemento C1q/metabolismo , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nefrite/genética , Nefrite/imunologia , Nefrite/patologia , Fagocitose/genética , Fagocitose/imunologia , Fosforilação , Ligação Proteica , Receptores Depuradores Classe F/metabolismo , Serina/metabolismoRESUMO
Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE. In this article, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+ dendritic cells initiates an IL-10 anti-inflammatory response mediated by the phosphorylation of STAT1 and STAT3. Unexpectedly, there was no significant difference in SCARF1 expression in samples of patients with SLE compared with healthy donor samples. However, we detected anti-SCARF1 autoantibodies in 26% of patients with SLE, which was associated with dsDNA Ab positivity. Furthermore, our data show a direct correlation of the levels of anti-SCARF1 in the serum and defects in the removal of ACs. Depletion of Ig restores efferocytosis in SLE serum, suggesting that defects in the removal of ACs are partially mediated by SCARF1 pathogenic autoantibodies. Our data demonstrate that human SCARF1 is an AC receptor in dendritic cells and plays a role in maintaining tolerance and homeostasis.
Assuntos
Autoanticorpos/imunologia , Imunomodulação , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Fagocitose/imunologia , Receptores Depuradores Classe F/genética , Animais , Autoanticorpos/sangue , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunomodulação/genética , Imunofenotipagem , Lúpus Eritematoso Sistêmico/diagnóstico , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Fosforilação , Fatores de Transcrição STAT/metabolismo , Receptores Depuradores Classe F/imunologia , Receptores Depuradores Classe F/metabolismoRESUMO
Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation.
Assuntos
Quimiocina CCL1/metabolismo , Quimiocina CCL8/metabolismo , Dermatite Atópica/imunologia , Pele/patologia , Células Th2/metabolismo , Transferência Adotiva , Animais , Sinalização do Cálcio/imunologia , Células Cultivadas , Quimiocina CCL1/genética , Quimiocina CCL1/imunologia , Quimiocina CCL8/genética , Quimiocina CCL8/imunologia , Quimiotaxia/genética , Quimiotaxia/imunologia , Clonagem Molecular , Modelos Animais de Doenças , Humanos , Interleucina-5/imunologia , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Retorno de Linfócitos/imunologia , Células Th2/imunologia , Células Th2/patologiaRESUMO
CXCL10 is an IFNγ-inducible chemokine implicated in the pathogenesis of type 1 diabetes. T-cells attracted to pancreatic islets produce IFNγ, but it is unclear what attracts the first IFNγ -producing T-cells in islets. Gut dysbiosis following administration of pathobionts induced CXCL10 expression in pancreatic islets of healthy non-diabetes-prone (C57BL/6) mice and depended on TLR4-signaling, and in non-obese diabetic (NOD) mice, gut dysbiosis induced also CXCR3 chemokine receptor in IGRP-reactive islet-specific T-cells in pancreatic lymph node. In amounts typical to low-grade endotoxemia, bacterial lipopolysaccharide induced CXCL10 production in isolated islets of wild type and RAG1 or IFNG-receptor-deficient but not type-I-IFN-receptor-deficient NOD mice, dissociating lipopolysaccharide-induced CXCL10 production from T-cells and IFNγ. Although mostly myeloid-cell dependent, also ß-cells showed activation of innate immune signaling pathways and Cxcl10 expression in response to lipopolysaccharide indicating their independent sensitivity to dysbiosis. Thus, CXCL10 induction in response to low levels of lipopolysaccharide may allow islet-specific T-cells imprinted in pancreatic lymph node to enter in healthy islets independently of IFN-g, and thus link gut dysbiosis to early islet-autoimmunity via dysbiosis-associated low-grade endotoxemia.
RESUMO
It has become increasingly clear that the terms used to define memory T cell subsets no longer accurately reflect our understanding of memory T cell biology. Here, we discuss the limitations of our current terminology and propose a new approach for defining memory T cell subsets.
Assuntos
Memória Imunológica , Subpopulações de Linfócitos T , Animais , Humanos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Terminologia como AssuntoRESUMO
Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release.
Assuntos
Movimento Celular/fisiologia , Sinaptotagminas/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Quimiotaxia , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , Receptores CXCR4/metabolismo , Sinaptotagmina II/metabolismo , Sinaptotagminas/genética , Linfócitos T/imunologiaRESUMO
The deposition of IgG autoantibodies in peripheral tissues and the subsequent activation of the complement system, which leads to the accumulation of the anaphylatoxin C5a in these tissues, is a common hallmark of diverse autoimmune diseases, including rheumatoid arthritis (RA) and pemphigoid diseases (PDs). C5a is a potent chemoattractant for granulocytes and mice deficient in its precursor C5 or its receptor C5aR1 are resistant to granulocyte recruitment and, consequently, to tissue inflammation in several models of autoimmune diseases. However, the mechanism whereby C5a/C5aR regulates granulocyte recruitment in these diseases has remained elusive. Mechanistic studies over the past five years into the role of C5a/C5aR1 in the K/BxN serum arthritis mouse model have provided novel insights into the mechanisms C5a/C5aR1 engages to initiate granulocyte recruitment into the joint. It is now established that the critical actions of C5a/C5aR1 do not proceed in the joint itself, but on the luminal endothelial surface of the joint vasculature, where C5a/C5aR1 mediate the arrest of neutrophils on the endothelium by activating ß2 integrin. Then, C5a/C5aR1 induces the release of leukotriene B4 (LTB4) from the arrested neutrophils. The latter, subsequently, initiates by autocrine/paracrine actions via its receptor BLT1 the egress of neutrophils from the blood vessel lumen into the interstitial. Compelling evidence suggests that this C5a/C5aR1-LTB4/BLT1 axis driving granulocyte recruitment in arthritis may represent a more generalizable biological principle critically regulating effector cell recruitment in other IgG autoantibody-induced diseases, such as in pemphigoid diseases. Thus, dual inhibition of C5a and LTB4, as implemented in nature by the lipocalin coversin in the soft-tick Ornithodoros moubata, may constitute a most effective therapeutic principle for the treatment of IgG autoantibody-driven diseases.
Assuntos
Doenças Autoimunes/imunologia , Complemento C5a/metabolismo , Inflamação/imunologia , Neutrófilos/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Animais , Autoanticorpos/metabolismo , Autoimunidade , Movimento Celular , Modelos Animais de Doenças , Humanos , Leucotrieno B4/metabolismo , Camundongos , Ativação de Neutrófilo , Transdução de SinaisRESUMO
Differentiation of naive CD4(+) T cells into T helper (Th) cells is a defining event in adaptive immunity. The cytokines and transcription factors that control Th cell differentiation are understood, but it is not known how this process is orchestrated within lymph nodes (LNs). Here we have shown that the CXCR3 chemokine receptor was required for optimal generation of interferon-γ (IFN-γ)-secreting Th1 cells in vivo. By using a CXCR3 ligand reporter mouse, we found that stromal cells predominately expressed the chemokine ligand CXCL9 whereas hematopoietic cells expressed CXCL10 in LNs. Dendritic cell (DC)-derived CXCL10 facilitated T cell-DC interactions in LNs during T cell priming while both chemokines guided intranodal positioning of CD4(+) T cells to interfollicular and medullary zones. Thus, different chemokines acting on the same receptor can function locally to facilitate DC-T cell interactions and globally to influence intranodal positioning, and both functions contribute to Th1 cell differentiation.
Assuntos
Diferenciação Celular/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Receptores CXCR3/metabolismo , Células Th1/citologia , Células Th1/imunologia , Animais , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Citocinas/biossíntese , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Interferon gama/biossíntese , Ligantes , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Camundongos , Camundongos Transgênicos , Ligação Proteica , Receptores CXCR3/genéticaRESUMO
Scratching triggers skin flares in atopic dermatitis. We demonstrate that scratching of human skin and tape stripping of mouse skin cause neutrophil influx. In mice, this influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.