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1.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Immunol ; 112: 399-405, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31299495

RESUMO

The spleen is an important secondary lymph organ. Splenomegaly induced by anemia could affect the function of spleen in immune responses. We observe that anemia induced in mice with reduced peripheral T cell trafficking to the spleen T cell zones as well as CCL21 and CCL19 expression. In accordance with previous research, we found that the production of EPO in the mice kidney was sharply increased post anemia. In addition, mice were injected with different doses of EPO. Our results show that with the increased dosage of EPO, the chemokine expression in the spleen is lowered with a decrease in peripheral T cell homing to the spleen T cell zones. At last, our results show that the anemia mice model administrated with anti-EPO antibody had a higher expression of spleen CCL19 and CCL21 and an increased count of periphery T cells trafficking to spleen T cell zones at day 3 post induction. These data indicate that anemia could disturb T cell movement in the spleen, which might further affect T cell immune response, with partial involvement of EPO.


Assuntos
Anemia/imunologia , Movimento Celular/imunologia , Eritropoetina/imunologia , Baço/imunologia , Esplenomegalia/imunologia , Linfócitos T/imunologia , Animais , Quimiocina CCL19/imunologia , Quimiocina CCL21/imunologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Nature ; 571(7763): 122-126, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31189952

RESUMO

Antibodies secreted into mucosal barriers serve to protect the host from a variety of pathogens, and are the basis for successful vaccines1. In type I mucosa (such as the intestinal tract), dimeric IgA secreted by local plasma cells is transported through polymeric immunoglobulin receptors2 and mediates robust protection against viruses3,4. However, owing to the paucity of polymeric immunoglobulin receptors and plasma cells, how and whether antibodies are delivered to the type II mucosa represented by the lumen of the lower female reproductive tract remains unclear. Here, using genital herpes infection in mice, we show that primary infection does not establish plasma cells in the lamina propria of the female reproductive tract. Instead, upon secondary challenge with herpes simplex virus 2, circulating memory B cells that enter the female reproductive tract serve as the source of rapid and robust antibody secretion into the lumen of this tract. CD4 tissue-resident memory T cells secrete interferon-γ, which induces expression of chemokines, including CXCL9 and CXCL10. Circulating memory B cells are recruited to the vaginal mucosa in a CXCR3-dependent manner, and secrete virus-specific IgG2b, IgG2c and IgA into the lumen. These results reveal that circulating memory B cells act as a rapidly inducible source of mucosal antibodies in the female reproductive tract.


Assuntos
Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Movimento Celular/imunologia , Memória Imunológica/imunologia , Vagina/citologia , Vagina/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 2/imunologia , Imunização , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR3/imunologia , Vagina/virologia
4.
Cancer Sci ; 110(8): 2357-2367, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169331

RESUMO

Dendritic cells (DCs) are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses against cancer. Tumor cells can escape from immune attack by secreting suppressive cytokines that solely or cooperatively impair the immune function of DCs. However, the underlying mechanisms are not fully defined. Vascular endothelial growth factor (VEGF) has been identified as a major cytokine in the tumor microenvironment. To elucidate the effects of VEGF on the motility and immune function of mature DCs (mDCs), the cells were treated with 50 ng/mL VEGF and investigated by proteomics and molecular biological technologies. The results showed that VEGF can impair the migration capacity and immune function of mDCs through the RhoA-cofilin1 pathway mediated by the VEGF receptor 2, suggesting impaired motility of mDCs by VEGF is one of the aspects of immune escape mechanisms of tumors. It is clinically important to understand the biological behavior of DCs and the immune escape mechanisms of tumor as well as how to improve the efficiency of antitumor therapy based on DCs.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Movimento Celular/imunologia , Células Dendríticas/metabolismo , Transdução de Sinais/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Fatores de Despolimerização de Actina/imunologia , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Proteína rhoA de Ligação ao GTP/imunologia
5.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
6.
Nat Immunol ; 20(6): 756-764, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110315

RESUMO

Emerging data show that tissue-resident memory T (TRM) cells play an important protective role at murine and human barrier sites. TRM cells in the epidermis of mouse skin patrol their surroundings and rapidly respond when antigens are encountered. However, whether a similar migratory behavior is performed by human TRM cells is unclear, as technology to longitudinally follow them in situ has been lacking. To address this issue, we developed an ex vivo culture system to label and track T cells in fresh skin samples. We validated this system by comparing in vivo and ex vivo properties of murine TRM cells. Using nanobody labeling, we subsequently demonstrated in human ex vivo skin that CD8+ TRM cells migrated through the papillary dermis and the epidermis, below sessile Langerhans cells. Collectively, this work allows the dynamic study of resident immune cells in human skin and provides evidence of tissue patrol by human CD8+ TRM cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Pele/imunologia , Animais , Antígenos/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Epiderme/imunologia , Epiderme/metabolismo , Imunofluorescência , Humanos , Camundongos , Especificidade de Órgãos/imunologia , Anticorpos de Domínio Único/imunologia , Pele/metabolismo , Vacinas de DNA/genética , Vacinas de DNA/imunologia
7.
Immunology ; 157(2): 173-184, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31013364

RESUMO

Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G-protein-coupled receptors (GPCRs). In addition, chemokines interact with cell-surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine interleukin-8/CXCL8, a prototypical neutrophil chemoattractant, is characterized by a long, highly positively charged GAG-binding C-terminal region, absent in most other chemokines. To examine whether the CXCL8 C-terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesized the wild-type CXCL8 C-terminal [CXCL8 (54-72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface plasmon resonance showed that Peptide 1, corresponding to the core CXCL8 GAG-binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8-induced calcium signalling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8-induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil-mediated inflammation based on modulation of chemokine-GAG binding.


Assuntos
Adesão Celular/imunologia , Movimento Celular/imunologia , Células Endoteliais/imunologia , Interleucina-8/imunologia , Neutrófilos/imunologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Neutrófilos/patologia , Peptídeos/imunologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-30961814

RESUMO

These last years, significant progress has been made in the design of strategies empowering T cells with efficient anti-tumor activities. Hence, adoptive T cell therapy and the use of monoclonal antibodies against the immunosuppressive surface molecules CTLA-4 and PD-1 appear as the most promising immunotherapies against cancer. One of the challenges ahead is to render these therapeutic interventions even more effective as a still elevated fraction of cancer patients is refractory to these treatments. A frequently overlooked determinant of the success of T cell-based immunotherapy relates to the ability of effector T cells to migrate into and within tumors, as well as to have access to tumor antigens. Here, we will focus on recent advances in understanding T cell trafficking into and within tumors. Both chemoattractant molecules and structural determinants are essential for regulating T cell motile behavior along with cellular interactions-mediated antigen recognition. In addition, we will review evidence that the microenvironment of advanced tumors creates multiple obstacles limiting T cells from migrating and making contact with their malignant targets. We will particularly focus on the extracellular matrix and tumor-associated macrophages that make tumors a hostile environment for T cell ability to contact and kill malignant cells. Finally, we will discuss possible strategies to restore a tumor microenvironment more favorable to T cell migration and functions with a special emphasis on approaches targeting the dysregulated extracellular matrix of growing tumors.


Assuntos
Transferência Adotiva/métodos , Imunoterapia/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/imunologia , Movimento Celular/imunologia , Quimiocinas/imunologia , Matriz Extracelular/metabolismo , Humanos , Macrófagos/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/transplante
9.
Nat Commun ; 10(1): 1850, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015429

RESUMO

Macrophage (Mϕ)-fibroblast interactions coordinate tissue repair after injury whereas miscommunications can result in pathological healing and fibrosis. We show that contracting fibroblasts generate deformation fields in fibrillar collagen matrix that provide far-reaching physical cues for Mϕ. Within collagen deformation fields created by fibroblasts or actuated microneedles, Mϕ migrate towards the force source from several hundreds of micrometers away. The presence of a dynamic force source in the matrix is critical to initiate and direct Mϕ migration. In contrast, collagen condensation and fiber alignment resulting from fibroblast remodelling activities or chemotactic signals are neither required nor sufficient to guide Mϕ migration. Binding of α2ß1 integrin and stretch-activated channels mediate Mϕ migration and mechanosensing in fibrillar collagen ECM. We propose that Mϕ mechanosense the velocity of local displacements of their substrate, allowing contractile fibroblasts to attract Mϕ over distances that exceed the range of chemotactic gradients.


Assuntos
Movimento Celular/imunologia , Matriz Extracelular/metabolismo , Colágenos Fibrilares/metabolismo , Fibroblastos/imunologia , Macrófagos/imunologia , Animais , Adesão Celular/imunologia , Células Cultivadas , Fibroblastos/metabolismo , Microscopia Intravital , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Vídeo , Cultura Primária de Células
10.
BMC Cancer ; 19(1): 261, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902074

RESUMO

BACKGROUND: The immune system is a crucial component in cancer progression or regression. Molecular iodine (I2) exerts significant antineoplastic effects, acting as a differentiation inductor and immune modulator, but its effects in antitumor immune response are not elucidated. METHODS: The present work analyzed the effect of I2 in human breast cancer cell lines with low (MCF-7) and high (MDA-MB231) metastatic potential under both in vitro (cell proliferation and invasion assay) and in vivo (xenografts of athymic nude mice) conditions. RESULTS: In vitro analysis showed that the 200 µM I2 supplement decreases the proliferation rate in both cell lines and diminishes the epithelial-mesenchymal transition (EMT) profile and the invasive capacity in MDA-MB231. In immunosuppressed mice, the I2 supplement impairs implantation (incidence), tumoral growth, and proliferation of both types of cells. Xenografts of the animals treated with I2 decrease the expression of invasion markers like CD44, vimentin, urokinase plasminogen activator and its receptor, and vascular endothelial growth factor; and increase peroxisome proliferator-activated receptor gamma. Moreover, in mice with xenografts, the I2 supplement increases the circulating level of leukocytes and the number of intratumoral infiltrating lymphocytes, some of them activated as CD8+, suggesting the activation of antitumor immune responses. CONCLUSIONS: I2 decreases the invasive potential of a triple negative basal cancer cell line, and under in vivo conditions the oral supplement of this halogen activates the antitumor immune response, preventing progression of xenografts from laminal and basal mammary cancer cells. These effects allow us to propose iodine supplementation as a possible adjuvant in breast cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Imunidade Celular/efeitos dos fármacos , Iodo/farmacologia , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Iodo/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Immunity ; 50(2): 493-504.e7, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737144

RESUMO

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.


Assuntos
Adaptação Fisiológica/imunologia , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia , Adaptação Fisiológica/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Colo/imunologia , Colo/metabolismo , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Pele/imunologia , Pele/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
12.
Nat Immunol ; 20(3): 257-264, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778250

RESUMO

Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited.


Assuntos
Dipeptidil Peptidase 4/imunologia , Eosinófilos/imunologia , Interleucina-33/imunologia , Neoplasias Experimentais/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimiocina CCL11/imunologia , Quimiocina CCL11/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Interleucina-33/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/prevenção & controle , Fosfato de Sitagliptina/farmacologia
13.
Proc Natl Acad Sci U S A ; 116(9): 3678-3687, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30733298

RESUMO

Infiltration of [Formula: see text] T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including triple-negative breast cancer (TNBC). However, the mechanisms underlying different infiltration levels are largely unknown. Here, we have characterized the spatial profile of [Formula: see text] T cells around tumor cell clusters (tightly connected tumor cells) in the core and margin regions in TNBC patient samples. We found that in some patients, the [Formula: see text] T cell density first decreases when moving in from the boundary of the tumor cell clusters and then rises again when approaching the center. To explain various infiltration profiles, we modeled the dynamics of T cell density via partial differential equations. We spatially modulated the diffusion/chemotactic coefficients of T cells (to mimic physical barriers) or introduced the localized secretion of a diffusing T cell chemorepellent. Combining the spatial-profile analysis and the modeling led to support for the second idea; i.e., there exists a possible chemorepellent inside tumor cell clusters, which prevents [Formula: see text] T cells from infiltrating into tumor cell clusters. This conclusion was consistent with an investigation into the properties of collagen fibers which suggested that variations in desmoplastic elements does not limit infiltration of [Formula: see text] T lymphocytes, as we did not observe significant correlations between the level of T cell infiltration and fiber properties. Our work provides evidence that [Formula: see text] T cells can cross typical fibrotic barriers and thus their infiltration into tumor clusters is governed by other mechanisms possibly involving a local repellent.


Assuntos
Linfócitos T CD8-Positivos/patologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Feminino , Humanos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/patologia
14.
Nature ; 566(7745): 503-508, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30787438

RESUMO

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein ß-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of ß-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, ß-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of ß-synuclein in provoking T-cell-mediated pathology of the central nervous system.


Assuntos
Substância Cinzenta/imunologia , Substância Cinzenta/patologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/patologia , Linfócitos T/imunologia , beta-Sinucleína/imunologia , Animais , Encéfalo/patologia , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica , Gliose/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Esclerose Múltipla Crônica Progressiva/sangue , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Ratos , Ratos Endogâmicos Lew , Linfócitos T/metabolismo , Linfócitos T/patologia , beta-Sinucleína/análise , beta-Sinucleína/genética , beta-Sinucleína/metabolismo
15.
Int Heart J ; 60(2): 451-456, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30799373

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) develops as a consequence of unresolved pulmonary embolism or clots in the pulmonary arteries. The obstruction not only reduces the area of the pulmonary vascular bed, but also elicits high pressure and high shear stress in the spared unobstructed arteries. Subsequent overflow of the small pulmonary arteries induces vascular remodeling, termed as overflow vasculopathy (OV). While the development of OV significantly contributes to the occurrence of pulmonary hypertension, its precise molecular mechanisms are yet to be determined.We established a novel murine pulmonary artery OV (PAOV) model, in which we resected left lung and induced redistribution of the cardiac output to the remaining pulmonary artery of the right lung. At 21 days after operation, mice showed an increase in the vascular media area, indicating the development of pulmonary arterial remodeling. In addition, right ventricular hypertrophy was detected in the PAOV model. Intriguingly, marked accumulation of F4/80-positive monocytes/macrophages was visualized in high-flow arteries, implying the role of an inflammatory process in the pathogenesis of overflow-induced vascular remodeling.


Assuntos
Hipertensão Pulmonar , Pulmão , Macrófagos/imunologia , Monócitos/imunologia , Remodelação Vascular/imunologia , Animais , Movimento Celular/imunologia , Modelos Animais de Doenças , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/fisiologia , Embolia Pulmonar/complicações
16.
Methods Cell Biol ; 150: 333-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30777183

RESUMO

Sea urchin larvae deploy a complex immune system in the context of relatively simple morphology. Several types of phagocytic or granular immune cells respond rapidly to microbes and microbial components within the body cavity. Many of these cells also respond to microbial disturbances in the gut lumen. In the course of immune response, hundreds of genes are up- and downregulated, many of which have homologs involved in immunity in other species. Thus, the larval sea urchin provides an experimentally advantageous model for investigating the response to immune challenge at the level of cell behavior and gene regulatory networks. Importantly, the morphological simplicity and optical clarity of these larvae allow studies to be carried out within the intact animal. Here, we outline techniques to probe and visualize the immune system of the feeding sea urchin larva, particularly for quantifying gene expression and cell migration as the animal responds to both pathogens and symbionts. Techniques addressed in this chapter include (1) exposure of larvae to microbes and microbial products in sea water and by blastocoelar microinjection, (2) time-lapse imaging of immune response, (3) isolation of culturable bacteria associated with feeding larvae, (4) quantification of larval associations with isolated bacterial strains and (5) preparation of secreted products from isolated bacteria for testing in larval culture.


Assuntos
Imunidade/imunologia , Larva/imunologia , Ouriços-do-Mar/imunologia , Animais , Movimento Celular/imunologia , Redes Reguladoras de Genes/imunologia
17.
J Nanobiotechnology ; 17(1): 14, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670029

RESUMO

BACKGROUND: T lymphocytes are highly dynamic elements of the immune system with a tightly regulated migration. T cell-based transfer therapies are promising therapeutic approaches which in vivo efficacy is often limited by the small proportion of administered cells that reaches the region of interest. Manipulating T cell localisation to improve specific targeting will increase the effectiveness of these therapies. Nanotechnology has been successfully used for localized release of drugs and biomolecules. In particular, magnetic nanoparticles (MNPs) loaded with biomolecules can be specifically targeted to a location by an external magnetic field (EMF). The present work studies whether MNP-loaded T cells could be targeted and retained in vitro and in vivo at a site of interest with an EMF. RESULTS: T cells were unable to internalize the different MNPs used in this study, which remained in close association with the cell membrane. T cells loaded with an appropriate MNP concentration were attracted to an EMF and retained in an in vitro capillary flow-system. MNP-loaded T cells were also magnetically retained in the lymph nodes after adoptive transfer in in vivo models. This enhanced in vivo retention was in part due to the EMF application and to a reduced circulating cell speed within the organ. This combined use of MNPs and EMFs did not alter T cell viability or function. CONCLUSIONS: These studies reveal a promising approach to favour cell retention that could be implemented to improve cell-based therapy.


Assuntos
Linfonodos , Nanopartículas de Magnetita , Linfócitos T , Animais , Movimento Celular/imunologia , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Campos Magnéticos , Camundongos , Camundongos Endogâmicos C57BL
18.
Immunology ; 156(4): 402-412, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30575026

RESUMO

Hyperactivation of the type 2 immune response is the major mechanism of allergic asthma, in which both group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells participate. Myeloid-derived suppressor cells (MDSCs) alleviate asthma by suppressing Th2 cells. However, the potential effects of MDSCs on the biological functions of ILC2s remain largely unknown. Here, we examined the roles of MDSCs (MDSCs) in the modulation of ILC2 function. Our results showed that polymorphonuclear (PMN)-MDSCs, but not monocytic (M-) MDSCs, effectively suppressed the cytokine production of ILC2s both in vitro and in vivo, thereby alleviating airway inflammation. Further analyses showed that cyclo-oxygenase-1 may mediate the suppressive effects of PMN-MDSCs on ILC2 responses. Our findings demonstrated that PMN-MDSCs may serve as a potent therapeutic target for the treatment of ILC2-driven allergic asthma.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Células Supressoras Mieloides/imunologia , Sistema Respiratório/imunologia , Animais , Asma/patologia , Movimento Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
19.
Front Biosci (Landmark Ed) ; 24: 18-34, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468645

RESUMO

G protein-coupled receptors (GPCRs) form a most diverse family of integral membrane proteins that mediate homeostatic and pathological processes, most notably by orchestrating cell distribution throughout the body, their infiltration, and time of presence in inflamed tissues. Here we discuss loss-of-orientation-effects in GPCR-mediated cell trafficking and migration and their impact on the phenotype of autoimmune diseases. In this context, we provide a systemic and integrative view of the contribution of abnormal GPCR expression as well as the levels of natural ligands and functional autoantibodies to the phenotype of autoimmune diseases. Currently, several studies propose that functional autoantibodies (including those targeting GPCRs) constitute an exclusively pathogenic or pathognomonic phenomenon. Here we reinforce the need of revising this point of view, and suggest that functional autoantibodies primary play a role in normal human physiology, while dysregulation of their functions causes autoimmune disease. Because patients with autoimmune diseases still suffer from severe morbidity and mortality rates, we consider expanding our knowledge on (patho)physiological roles of GPCR as a prerequisite for the development of novel specific therapeutic modalities.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Movimento Celular/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Animais , Autoanticorpos/metabolismo , Doenças Autoimunes/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Modelos Imunológicos , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
20.
Front Immunol ; 9: 2739, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538702

RESUMO

Immune responses are dependent on the recruitment of leukocytes to the site of inflammation. The classical leukocyte recruitment cascade, consisting of capture, rolling, arrest, adhesion, crawling, and transendothelial migration, is thoroughly studied but mostly in model systems, such as the cremasteric microcirculation. This cascade paradigm, which is widely accepted, might be applicable to many tissues, however recruitment mechanisms might substantially vary in different organs. Over the last decade, several studies shed light on organ-specific mechanisms of leukocyte recruitment. An improved awareness of this matter opens new therapeutic windows and allows targeting inflammation in a tissue-specific manner. The aim of this review is to summarize the current understanding of the leukocyte recruitment in general and how this varies in different organs. In particular we focus on neutrophils, as these are the first circulating leukocytes to reach the site of inflammation. Specifically, the recruitment mechanism in large arteries, as well as vessels in the lungs, liver, and kidney will be addressed.


Assuntos
Aorta/imunologia , Movimento Celular/imunologia , Rim/imunologia , Fígado/imunologia , Pulmão/imunologia , Neutrófilos/imunologia , Migração Transendotelial e Transepitelial/imunologia , Animais , Humanos , Inflamação/imunologia , Leucócitos/imunologia
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