RESUMO
PDAC is a typical "cold tumor" characterized by low immune cell infiltration and a suppressive immune microenvironment. We previously observed the existence of a rare group of follicular helper T cells (Tfh) that could enhance antitumor immune responses by recruiting other immune cells in PDAC. In this study, we ectopically expressed BCL6 in CD4+ T cells, and successfully induced Tfh-like transdifferentiation in vitro. This strategy provided abundant Tfh-like cells (iTfhs) that can recruit CD8+ T cells like endogenous Tfhs. Subsequently, Chimeric Antigen Receptors (CARs) against both MSL (Mesothelin) and EPHA2 (Ephrin receptor A2) were used to modify iTfh cells, and the CAR-iTfh cells significantly improved infiltration and antitumor cytotoxicity of co-cultured CD8+ T cells. After that, combinatory administration of CAR-iTfh & CAR-CD8 T cell therapy displayed a better effect in repressing the PDAC tumors in xenograft mouse models, compared to conventional CAR-CD4 & CAR-CD8 combinations, and the models received the CAR-iTfh & CAR-CD8 T cells displayed a significantly improved survival rate. Our study revealed the plasticity of Thelper differentiation, expanded the source of Tfh-like cells for cell therapy, and demonstrated a novel and potentially more efficient cellular composition for CAR-T therapy.
Assuntos
Transdiferenciação Celular , Imunoterapia Adotiva , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-bcl-6 , Receptores de Antígenos Quiméricos , Animais , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Camundongos , Imunoterapia Adotiva/métodos , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Transdiferenciação Celular/imunologia , Linfócitos T CD4-Positivos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Receptor EphA2/imunologia , Receptor EphA2/genética , Linfócitos T Auxiliares-Indutores/imunologia , FemininoRESUMO
The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.
Assuntos
Transdiferenciação Celular , Interferon gama , Interleucina-17 , Psoríase , Células Th17 , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/imunologia , Células Th17/imunologiaRESUMO
Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. Therefore, targeted therapy directed against androgen synthesis or AR activation is broadly used and continually improved. However, a subset of patients eventually progresses to castration-resistant disease. To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). Here, we review the highly complex processes contributing to NED. Genetic, epigenetic, transcriptional aberrations and posttranscriptional modifications are highlighted and the potential interplay of the different factors is discussed. Background Aggressive variant prostate cancer (AVPC) with traits of neuroendocrine differentiation emerges in a rising number of patients in recent years. Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. This complicates both diagnosis and treatment of this very aggressive disease. We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation. However, the complexity of the diverse molecular pathways has not been captured completely, yet. This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far.
Assuntos
Transdiferenciação Celular/imunologia , Neoplasias da Próstata/fisiopatologia , Humanos , MasculinoRESUMO
Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA-CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.
Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T Reguladores/fisiologia , Antígeno B7-H1/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Estudos de Coortes , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Memória Imunológica/fisiologia , Antígenos Comuns de Leucócito/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/fisiologia , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/metabolismoRESUMO
Cultured peritoneal macrophages from intact (control) and BCG-infected (experiment) male BALB/c mice were studied 90 days after infection. Polarization of macrophages by M1 (expression of GM-CSF, IFNγ, and CD16/32) and M2 (expression of bFGF and CD36) differentiation pathways was studied with consideration for their the nuclearity class. Mononuclear cells predominated (90% and higher) in macrophage cultures of both groups and presumably, were presented by mainly epithelioid cells. The results indicated polarization of mononuclear and multinuclear macrophages in the M2 direction under conditions of BCG granulomatosis and a higher initial M2 polarization of binuclear macrophages. In control cultures, the ratio of M2 to M1 macrophages was 0.57, in experimental cultures this ratio was 1.6. It seems that long persistence of Mycobacterium tuberculosis in macrophages served as a factor stimulating the plastic processes and transformation of macrophages into epithelioid cells that form the "core" of granulomas and their enlargement upon incorporation of macrophages.
Assuntos
Células Epitelioides/patologia , Regulação da Expressão Gênica/imunologia , Macrófagos Peritoneais/patologia , Mycobacterium bovis/crescimento & desenvolvimento , Tuberculose/patologia , Animais , Antígenos CD36/genética , Antígenos CD36/imunologia , Diferenciação Celular , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Células Epitelioides/imunologia , Células Epitelioides/microbiologia , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interferon gama/genética , Interferon gama/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/patogenicidade , Cultura Primária de Células , Receptores de IgG/genética , Receptores de IgG/imunologia , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/microbiologiaRESUMO
Germinal center-associated nuclear protein (GANP) is a unique and multifunctional protein that plays a critical role in cell biology, neurodegenerative disorders, immunohematology, and oncogenesis. GANP is an orthologue of Saccharomyces Sac3, one of the components of the transcription export 2 (TREX-2) complex and a messenger RNA (mRNA) nuclear export factor. GANP is widely conserved in all mammals, including humans. Although GANP was originally discovered as a molecule upregulated in the germinal centers of secondary lymphoid follicles in peripheral lymphoid organs, it is expressed ubiquitously in many tissues. It serves numerous functions, including making up part of the mammalian TREX-2 complex; mRNA nuclear export via nuclear pores; prevention of R-loop formation, genomic instability, and hyper-recombination; and B-cell affinity maturation. In this review, we first overview the extensive analyses that have revealed the basic functions of GANP and its ancestor molecule Sac3, including mRNA nuclear export and regulation of R-loop formation. We then describe how aberrant expression of GANP is significantly associated with cancer development. Moreover, we discuss a crucial role for GANP in B-cell development, especially affinity maturation in germinal centers. Finally, we illustrate that overexpression of GANP in B cells leads to lymphomagenesis resembling Hodgkin lymphoma derived from germinal center B cells, and that GANP may be involved in transdifferentiation of B cells to macrophages, which strongly affects Hodgkin lymphomagenesis.
Assuntos
Acetiltransferases/imunologia , Carcinogênese/imunologia , Neoplasias Hematológicas/imunologia , Doença de Hodgkin/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Neoplasias/imunologia , Transporte Ativo do Núcleo Celular/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Carcinogênese/patologia , Transdiferenciação Celular/imunologia , Centro Germinativo/imunologia , Centro Germinativo/patologia , Neoplasias Hematológicas/patologia , Doença de Hodgkin/patologia , Humanos , Macrófagos/imunologia , Macrófagos/patologia , RNA Mensageiro/imunologia , RNA Neoplásico/imunologiaAssuntos
Transdiferenciação Celular , Imunoterapia/efeitos adversos , Linfoma de Célula do Manto/terapia , Segunda Neoplasia Primária/etiologia , Sarcoma/etiologia , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Reprogramação Celular/fisiologia , Terapia Combinada , Epigênese Genética/fisiologia , Epigenoma/imunologia , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Segunda Neoplasia Primária/diagnóstico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Transplante Autólogo/efeitos adversos , Células Tumorais CultivadasRESUMO
Inflammatory bowel disease (IBD) is a chronic disorder manifested as Crohn's disease (CD) and ulcerative colitis (UC) characterized by intestinal inflammation and involves a dysregulated immune response against commensal microbiota through the activation of CD4 T helper cells. T helper cell differentiation to effector or regulatory phenotypes is controlled by cytokine networks and transcriptional regulators. Distinct polarized T helper cells are able to alter their phenotypes to adapt to diverse and fluctuating physiological environments. T helper cells exhibit intrinsic instability and flexibility to express cytokines of other lineages or transdifferentiate from one T helper cell type to another in response to various perturbations from physiological cytokine milieu as a means of promoting local immunity in response to injury or ensure tissue homeostasis. Furthermore, functional plasticity and diversity of T helper cells are associated with pathogenicity and are critical for immune homeostasis and prevention of autoimmunity. In this review, we provide deeper insights into the combinatorial extrinsic and intrinsic signals that control plasticity and transdifferentiation of T helper cells and also highlight the potential of exploiting the genetic reprogramming plasticity of T helper cells in the treatment of IBD.
Assuntos
Transdiferenciação Celular/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transdiferenciação Celular/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Citocinas/metabolismo , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismoRESUMO
The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T-cell development, homeostasis, activation, and effector-cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T-cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T-cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.
Assuntos
Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Transdiferenciação Celular/imunologia , Citocinas/metabolismo , Citoesqueleto/metabolismo , Metabolismo Energético , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
BACKGROUND AND AIMS: During liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate into proliferative and fibrogenic activated myofibroblastic phenotype (activated hepatic stellate cell; aHSCs) expressing smooth muscle α-actin (αSMA) and platelet-derived growth factor beta receptor (PDGFßR). Their interactions with gut-derived bacterial lipopolysaccharide (LPS) are implicated in hepatic fibrogenesis. However, LPS can also attenuate fibrogenic characteristics of aHSCs. APPROACH AND RESULTS: We examined molecular mechanisms of antifibrogenic effects of LPS on aHSCs in vitro and in vivo. Culture-activated rat HSCs were exposed to 0-100 ng/mL of LPS or its active component, diphosphoryl-lipid A (DPLA), and parameters of fibrosis and inflammatory cytokines/chemokines were determined by qRT-PCR, western, and immunohistochemical analyses. In vivo, HSCs were activated by repeated CCl4 administration to rats every 3 days for 3 or 8 weeks, then challenged with LPS (5 mg/kg; IP). HSCs were isolated 24 hours later, and fibrogenic/inflammatory parameters were analyzed. LPS induced phenotypic changes in aHSCs (rounding, size reduction) and loss of proliferation. LPS down-regulated expression of αSMA, PDGFßR, transforming growth factor beta receptor 1 (TGFßR1), collagen 1α1 (Col1α1), and fibronectin while up-regulating tumor necrosis factor alpha, interleukin-6, and C-X-C motif chemokine ligand 1 expression. LPS did not increase peroxisome proliferation-activated receptor gamma expression or lipid accumulation typical of qHSCs. DPLA elicited the same effects as LPS on aHSCs, indicating specificity, and monophosphoryl lipid A down-regulated fibrogenic markers, but elicited very weak inflammatory response. LPS down-regulated the expression of cMyb, a transcription factor for αSMA, and up-regulated small mother against decapentaplegic (SMAD)7 and CCAAT/enhancer-binding protein (C/EBP)δ, the transcriptional inhibitors of Col1α1 expression. In vivo LPS treatment of aHSCs inhibited their proliferation, down-regulated PDGFßR, αSMA, TGFßR1, Col1α1, and cMyb expression, and increased expression of SMAD7, C/EBPα, and C/EBPδ. CONCLUSIONS: In conclusion, LPS induces a unique phenotype in aHSCs associated with down-regulation of key fibrogenic mechanisms and thus may have an important role in limiting fibrosis.
Assuntos
Regulação da Expressão Gênica/imunologia , Células Estreladas do Fígado/imunologia , Lipídeo A/análogos & derivados , Cirrose Hepática Experimental/imunologia , Fígado/patologia , Animais , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Transdiferenciação Celular/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Regulação para Baixo , Inativação Gênica , Células Estreladas do Fígado/patologia , Humanos , Lipídeo A/imunologia , Lipídeo A/metabolismo , Fígado/citologia , Fígado/imunologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Camundongos , Camundongos Knockout , Miofibroblastos/imunologia , Miofibroblastos/patologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myb/metabolismo , Ratos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína Smad7/genética , Proteína Smad7/metabolismo , Regulação para Cima/imunologiaRESUMO
Resident cardiac macrophages play important roles in homeostasis, maintenance of cardiac function, and tissue repair. After cardiac injury, monocytes infiltrate the tissue, undergo phenotypic and functional changes, and are involved in inflammatory injury and functional remodelling. However, the fate of cardiac infiltrating/polarized macrophages and the relationship between these cells and resident cardiac macrophage replenishment following injury remain unclear. Our results showed that angiotensin II induces cardiac fibroblast transdifferentiation into cardiac myofibroblasts (MFBs). In cocultures with MFBs and murine macrophages, the MFBs promoted macrophage polarization to M1 phenotype, followed by selective apoptosis, which was associated with TNF/TNFR1 axis and independent of NO production. Surprisingly, after 36 h of coculture, the surviving macrophages were converted to M2 phenotype and settled in heart, which was dependent on leptin produced by MFBs or polarized macrophages via the PI3K or Akt pathway. CCR2+ CD45.2+ cells adoptively transferred into CD45.1+ mice with viral myocarditis, differentiated into CD45.2+ CCR2+ CX3CR1+ M2 cells during the resolution of inflammation and settled within the heart. Our data highlight a novel mechanism related to the renewal or replenishment of cardiac resident macrophages following cardiac injury; and suggest that transdifferentiation of cardiac fibroblasts may promote the resolution of inflammation.
Assuntos
Transdiferenciação Celular/imunologia , Fibroblastos/imunologia , Macrófagos/imunologia , Miocardite/imunologia , Miocárdio/imunologia , Transdução de Sinais/imunologia , Animais , Transdiferenciação Celular/genética , Fibroblastos/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocardite/genética , Miocardite/patologia , Miocárdio/patologia , Transdução de Sinais/genéticaRESUMO
The small intestinal (SI) epithelium harbors a heterogeneous population of lymphocytes that mediate mucosal damage and repair in celiac disease (CD). The composition and roles of human proximal SI intra-epithelial innate lymphoid cells (ILCs), and their alterations in CD, are not well understood. We report that duodenal intra-epithelial ILCs predominantly consist of natural killer (NK)p44+ CD127- cytotoxic ILC1s and NKp44- CD127+ helper ILC1s, while ILC3s only represent a minor population. In patients with newly diagnosed or active CD (ACD) and refractory CD type 1 (RCD I), the frequency of SI NKp44+ ILCs is decreased, with restoration of NKp44+ ILC frequency observed in patients adhering to a gluten-free diet who show evidence of mucosal healing. Moreover, the frequency of SI NKp44- ILCs is increased in ACD and RCD I patients and correlates with the severity of villous atrophy and epithelial damage, as assessed by serum levels of fatty acid binding protein 2 (FABP2). We show that the ILC alterations in CD represent a phenotypic shift of cytotoxic ILC1s rather than an increase in helper ILC1s or transdifferentiation of ILC1s to ILC3s, and activation-induced loss of NKp44 by cytotoxic ILC1s is associated with increased interferon (IFN)-γ expression and release of lytic granules. These findings suggest that intra-epithelial NKp44- CD127- cytotoxic ILC1s may contribute to mucosal damage in CD.
Assuntos
Doença Celíaca , Transdiferenciação Celular/imunologia , Duodeno , Mucosa Intestinal , Linfócitos , Adolescente , Adulto , Doença Celíaca/imunologia , Doença Celíaca/patologia , Criança , Pré-Escolar , Duodeno/imunologia , Duodeno/patologia , Feminino , Humanos , Imunidade Inata , Lactente , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Linfócitos/imunologia , Linfócitos/patologia , MasculinoRESUMO
The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1ß plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1ß and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.
Assuntos
Diferenciação Celular/imunologia , Transdiferenciação Celular/imunologia , Fator de Transcrição Ikaros/imunologia , Células Matadoras Naturais/imunologia , Lenalidomida/imunologia , Células Cultivadas , Humanos , Imunidade Inata/imunologia , Fatores Reguladores de Interferon/imunologia , Interleucina-12/imunologia , Interleucina-1beta/imunologia , Linfócitos/imunologiaRESUMO
In the last decade several studies employing stem cells-based therapies have been investigated as an optional treatment for multiple sclerosis. Several preclinical and few clinical studies tested the efficacy of mesenchymal stem cells as a potent candidate for such therapies. Here we suggest the option of "neuralization" of classical mesenchymal stem cells as a cellular structure that resembles neural stem cells as well as there differentiation by a unique procedure towards terminally differentiated neural cells suggesting that this cell population may be appropriate for clinical application in the CNS. We investigated whether neuralized MSC (NMSC) could promote repair and recovery after injection into mice with EAE. Injection of NMSC and differentiated NMSC starting at the onset of the chronic phase of disease improved neurological function compared to controls as well as compared to naïve MSC. Injection of NMSC and mainly differentiated correlated with a reduction in the inflammation as well as in the axonal loss/damage and reduced area of demyelination. These observations suggest that NMSC and differentiated NMSC may suggest a more potent cell-based therapy that naïve MSC in the treatment arsenal of multiple sclerosis.
Assuntos
Transdiferenciação Celular/imunologia , Fatores Estimuladores de Colônias/farmacologia , Encefalomielite Autoimune Experimental/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Esclerose Múltipla/terapia , Animais , Técnicas de Cultura de Células , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Camundongos , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Células-Tronco Neurais/imunologia , Esferoides Celulares , Resultado do TratamentoRESUMO
Osteoimmunological studies have revealed that T cells exert a powerful impact on the formation and activity of osteoclasts and bone remodeling. Evidence demonstrates that immature dendritic cells (iDCs) are more efficient transdifferentiating into osteoclasts (OCs) than monocytes. However, whether Vγ9Vδ2 T (γδ T) cells stimulate or inhibit iDC transdifferentiation into OCs has never been reported. The aim of the present study was to investigate the effects of γδ T cells on this transdifferentiation process. γδ T cells and iDCs were isolated from the peripheral blood of healthy volunteers separately and were cocultured with Transwelll inserts, with γδ T cells in the upper chamber and iDCs in the lower chamber. IDCs were treated with macrophagecolony stimulating factor and receptor activator of nuclear factorκB (RANK) ligand. Tartrate resistant acid phosphatase (TRAP) assay and dentine resorption assay were performed to detect OC formation and their resorption capacity, respectively. The mRNA expression of OCs was examined using a microarray and real timequantitative polymerase chain reaction to trace the changes during iDC transdifferentiation into OCs. The results demonstrated that γδ T cells significantly inhibited the generation of the TRAPpositive OCs from iDCs and their resorption capacity. The microarray analysis identified decreased expression level of Fos protooncogene AP1 transcription factor subunit (cFos), ATPase H+ transporting V0 subunit d (ATP6V0D2) and cathepsin K when iDCs were cocultured with γδ T cells. These genes are associated with OC differentiation, indicating that γδ T cells suppressed iDCs osteoclastogenesis by downregulation of the RANK/cFos/ATP6V0D2 signaling pathway. The present findings provide novel insights into the interactions between human γδ T cells and iDCs, and demonstrate that γδ T cells are capable of inhibiting OC formation and their activity via downregulation of genes associated with OC differentiation.
Assuntos
Transdiferenciação Celular/imunologia , Células Dendríticas/imunologia , Osteoclastos/imunologia , Proteínas Proto-Oncogênicas c-fos/imunologia , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , ATPases Vacuolares Próton-Translocadoras/imunologia , Células Dendríticas/patologia , Humanos , Osteoclastos/patologia , Linfócitos T/patologiaRESUMO
Host lipid metabolism is an important target for subversion by pathogenic mycobacteria such as Mycobacterium tuberculosis. The appearance of foam cells within the granuloma are well-characterised effects of chronic tuberculosis. The zebrafish-Mycobacterium marinum infection model recapitulates many aspects of human-M. tuberculosis infection and is used as a model to investigate the structural components of the mycobacterial granuloma. Here, we demonstrate that the zebrafish-M. marinum granuloma contains foam cells and that the transdifferentiation of macrophages into foam cells is driven by the mycobacterial ESX1 pathogenicity locus. This report demonstrates conservation of an important aspect of mycobacterial infection across species.
Assuntos
Células Espumosas/fisiologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Mycobacterium marinum/imunologia , Tuberculose/imunologia , Peixe-Zebra/fisiologia , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Transdiferenciação Celular/imunologia , Modelos Animais de Doenças , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Metabolismo dos Lipídeos/imunologia , Macrófagos/fisiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologiaRESUMO
Innate immune cells express danger-associated molecular pattern (DAMP) receptors, T-cell costimulation/coinhibition receptors, and major histocompatibility complex II (MHC-II). We have recently proposed that endothelial cells can serve as innate immune cells, but the molecular mechanisms involved still await discovery. Here, we investigated whether human aortic endothelial cells (HAECs) could be transdifferentiated into innate immune cells by exposing them to hyperlipidemia-up-regulated DAMP molecules, i.e. lysophospholipids. Performing RNA-seq analysis of lysophospholipid-treated HAECs, we found that lysophosphatidylcholine (LPC) and lysophosphatidylinositol (LPI) regulate largely distinct gene programs as revealed by principal component analysis. Metabolically, LPC up-regulated genes that are involved in cholesterol biosynthesis, presumably through sterol regulatory element-binding protein 2 (SREBP2). By contrast, LPI up-regulated gene transcripts critical for the metabolism of glucose, lipids, and amino acids. Of note, we found that LPC and LPI both induce adhesion molecules, cytokines, and chemokines, which are all classic markers of endothelial cell activation, in HAECs. Moreover, LPC and LPI shared the ability to transdifferentiate HAECs into innate immune cells, including induction of potent DAMP receptors, such as CD36 molecule, T-cell costimulation/coinhibition receptors, and MHC-II proteins. The induction of these innate-immunity signatures by lysophospholipids correlated with their ability to induce up-regulation of cytosolic calcium and mitochondrial reactive oxygen species. In conclusion, lysophospholipids such as LPC and LPI induce innate immune cell transdifferentiation in HAECs. The concept of prolonged endothelial activation, discovered here, is relevant for designing new strategies for managing cardiovascular diseases.
Assuntos
Aorta/imunologia , Transdiferenciação Celular/imunologia , Endotélio Vascular/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Lisofosfolipídeos/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Cálcio/metabolismo , Células Cultivadas , Citosol/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) - transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myoï¬broblasts - is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.
Assuntos
Transdiferenciação Celular/fisiologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Citocinas/imunologia , Epigênese Genética/fisiologia , Células Estreladas do Fígado/imunologia , Humanos , Imunidade Inata , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Transdução de Sinais/fisiologiaRESUMO
Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3+ cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A+Foxp3+ and ex-Th17 Foxp3+ cells are converted from IL-17A+Foxp3neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A+Foxp3+ cells. Transcriptome analysis and flow cytometry of IL-17A+Foxp3+ cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17-Treg cells in cancer immunotherapy.
Assuntos
Adenocarcinoma de Células Claras/imunologia , Tolerância Imunológica/imunologia , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Transdiferenciação Celular/imunologia , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Homeostase/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Inflamação/imunologia , Cadeias alfa de Integrinas/metabolismo , Cadeias beta de Integrinas/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-17/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fenótipo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Subpopulações de Linfócitos TRESUMO
Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.