Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
Annu Rev Immunol ; 42(1): 317-345, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38941605

RESUMO

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.


Assuntos
Memória Imunológica , Células T de Memória , Humanos , Animais , Células T de Memória/imunologia , Células T de Memória/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vigilância Imunológica
2.
Nat Immunol ; 23(8): 1236-1245, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35882933

RESUMO

Tissue-resident memory T cells (TRM cells) provide rapid and superior control of localized infections. While the transcription factor Runx3 is a critical regulator of CD8+ T cell tissue residency, its expression is repressed in CD4+ T cells. Here, we show that, as a direct consequence of this Runx3-deficiency, CD4+ TRM cells lacked the transforming growth factor (TGF)-ß-responsive transcriptional network that underpins the tissue residency of epithelial CD8+ TRM cells. While CD4+ TRM cell formation required Runx1, this, along with the modest expression of Runx3 in CD4+ TRM cells, was insufficient to engage the TGF-ß-driven residency program. Ectopic expression of Runx3 in CD4+ T cells incited this TGF-ß-transcriptional network to promote prolonged survival, decreased tissue egress, a microanatomical redistribution towards epithelial layers and enhanced effector functionality. Thus, our results reveal distinct programming of tissue residency in CD8+ and CD4+ TRM cell subsets that is attributable to divergent Runx3 activity.


Assuntos
Memória Imunológica , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fator de Crescimento Transformador beta/metabolismo
3.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
4.
Immunity ; 2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39406245

RESUMO

Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor ß (TGF-ß) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-ß-independent tissue residency program in the liver and synergizing with TGF-ß to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.

5.
Immunity ; 56(7): 1664-1680.e9, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37392736

RESUMO

Memory CD8+ T cells can be broadly divided into circulating (TCIRCM) and tissue-resident memory T (TRM) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of TCIRCM and TRM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in TCIRCM and TRM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within TCIRCM and TRM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of TCIRCM or TRM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions.


Assuntos
Linfócitos T CD8-Positivos , Células T de Memória , Camundongos , Animais , Linhagem da Célula , Memória Imunológica
6.
Nat Immunol ; 19(2): 183-191, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29311695

RESUMO

Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Pele/imunologia , Animais , Proliferação de Células/fisiologia , Herpes Simples/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
7.
Trends Immunol ; 44(9): 663-664, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37591711

RESUMO

Human tissue-resident memory T (TRM) cells seeded early in life undergo an age-associated functional maturation and residency acquisition throughout childhood.


Assuntos
Envelhecimento , Células T de Memória , Criança , Humanos , Especificidade de Órgãos
8.
Trends Immunol ; 43(4): 280-282, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35272933

RESUMO

Efficient generation of tissue-resident memory T (TRM) cells is essential for long-lived immune protection in barrier tissues. Peng et al. now show that the costimulatory molecule ICOS enhances CD8+ TRM cell lodgment by promoting early tissue retention.


Assuntos
Internato e Residência , Bandagens , Linfócitos T CD8-Positivos/imunologia , Humanos , Memória Imunológica/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis , Fatores de Transcrição
9.
J Immunol ; 199(7): 2451-2459, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28855310

RESUMO

Infection or inflammation of the skin recruits effector CD8+ T cells that enter the epidermis and form populations of long-lived tissue-resident memory T (TRM) cells. These skin TRM cells migrate within the constrained epidermal environment by extending multiple dynamic dendritic projections and squeezing between keratinocytes to survey the tissue for pathogens. In this study, we examined the signals required for this distinctive mode of T cell migration by inhibiting key cytoskeletal components and performing intravital two-photon microscopy to visualize TRM cell behavior. We found that TRM cell motility and dendrite formation required an intact actomyosin cytoskeleton and the Rho-associated coiled-coil containing kinases. We also identified an essential role for microtubules for maintaining skin TRM cell shape and cellular integrity. We reveal a role for pertussis toxin-sensitive signaling for TRM cell dendritic morphology and migration that is independent of CXCR3 or CXCR6, or the skin-selective chemokine receptors CCR10 and CCR8. However, we found that CXCR6 and CCR10 expression by CD8+ T cells was required for the optimal formation of memory T cell populations, in particular TRM cell populations in the skin.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Epiderme/imunologia , Memória Imunológica , Receptores de Quimiocinas/metabolismo , Pele/imunologia , Actomiosina/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/fisiologia , Células Epidérmicas , Microscopia Intravital/métodos , Camundongos , Microtúbulos/metabolismo , Toxina Pertussis/metabolismo , Receptores CCR10/genética , Receptores CCR10/metabolismo , Receptores CCR8/metabolismo , Receptores CXCR/genética , Receptores CXCR/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR6 , Receptores de Quimiocinas/genética , Transdução de Sinais , Pele/anatomia & histologia , Pele/citologia , Quinases Associadas a rho/metabolismo
10.
Mol Ther ; 24(6): 1135-1149, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27019998

RESUMO

Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/transplante , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Gangliosídeos/imunologia , Humanos , Ativação Linfocitária , Melanoma/imunologia , Camundongos , Metástase Neoplásica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Immunol Cell Biol ; 93(8): 694-704, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25823995

RESUMO

The role of intracellular calcium ion oscillations in T-cell physiology is being increasingly appreciated by studies that describe how unique temporal and spatial calcium ion signatures can control different signalling pathways. Within this review, we provide detailed mechanisms of calcium ion oscillations, and emphasise the pivotal role that calcium signalling plays in directing crucial events pertaining to T-cell functionality. We also describe methods of calcium ion quantification, and take the opportunity to discuss how a deeper understanding of calcium signalling combined with new detection and quantification methodologies can be used to better design immunotherapies targeting T-cell responses.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Íons/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Humanos , Espaço Intracelular/metabolismo , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia
12.
J Nat Prod ; 78(12): 3031-40, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26636180

RESUMO

The purpose of this study was to assess the biofilm-removing efficacy and inflammatory activity of a serrulatane diterpenoid, 8-hydroxyserrulat-14-en-19-oic acid (1), isolated from the Australian medicinal plant Eremophila neglecta. Biofilm breakup activity of compound 1 on established Staphylococcus epidermidis and Staphylococcus aureus biofilms was compared to the antiseptic chlorhexidine and antibiotic levofloxacin. In a time-course study, 1 was deposited onto polypropylene mesh to mimic a wound dressing and tested for biofilm removal. The ex-vivo cytotoxicity and effect on lipopolysaccharide-induced pro-inflammatory cytokine release were studied in mouse primary bone-marrow-derived macrophage (BMDM) cells. Compound 1 was effective in dispersing 12 h pre-established biofilms with a 7 log10 reduction of viable bacterial cell counts, but was less active against 24 h biofilms (approximately 2 log10 reduction). Compound-loaded mesh showed dosage-dependent biofilm-removing capability. In addition, compound 1 displayed a significant inhibitory effect on tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) secretion from BMDM cells, but interleukin-1 beta (IL-1ß) secretion was not significant. The compound was not cytotoxic to BMDM cells at concentrations effective in removing biofilm and lowering cytokine release. These findings highlight the potential of this serrulatane diterpenoid to be further developed for applications in wound management.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Eremophila (Planta)/química , Plantas Medicinais/química , Animais , Antibacterianos/química , Austrália , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Citocinas/farmacologia , Diterpenos/química , Relação Dose-Resposta a Droga , Interleucina-1beta/efeitos dos fármacos , Interleucina-6 , Levofloxacino/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Scrophulariaceae , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos
13.
Mucosal Immunol ; 16(4): 446-461, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37182737

RESUMO

Mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδT cells are collectively referred to as 'unconventional T cells' due to their recognition of non-peptide antigens and restriction to MHC-I-like molecules. However, the factors controlling their widely variable frequencies between individuals and organs are poorly understood. We demonstrated that MAIT cells are increased in NKT or γδT cell-deficient mice and highly expand in mice lacking both cell types. TCRα repertoire analysis of γδT cell-deficient thymocytes revealed altered Trav segment usage relative to wild-type thymocytes, highlighting retention of the Tcra-Tcrd locus from the 129 mouse strain used to generate Tcrd-/- mice. This resulted in a moderate increase in distal Trav segment usage, including Trav1, potentially contributing to increased generation of Trav1-Traj33+ MAIT cells in the Tcrd-/- thymus. Importantly, adoptively transferred MAIT cells underwent increased homeostatic proliferation within NKT/gdT cell-deficient tissues, with MAIT cell subsets exhibiting tissue-specific homing patterns. Our data reveal a shared niche for unconventional T cells, where competition for common factors may be exploited to collectively modulate these cells in the immune response. Lastly, our findings emphasise careful assessment of studies using NKT or γδT cell-deficient mice when investigating the role of unconventional T cells in disease.


Assuntos
Células T Invariantes Associadas à Mucosa , Células T Matadoras Naturais , Camundongos , Animais , Receptores de Antígenos de Linfócitos T alfa-beta , Timo , Receptores de Antígenos de Linfócitos T gama-delta
14.
Cancer Cell ; 41(3): 585-601.e8, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36827978

RESUMO

CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Memória Imunológica , Fenótipo , Prognóstico , Linfócitos do Interstício Tumoral
15.
Science ; 382(6674): 1073-1079, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38033053

RESUMO

Skin-resident CD8+ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Células T de Memória , Pele , Linfócitos T CD8-Positivos/imunologia , Células T de Memória/imunologia , Pele/imunologia , Humanos , Células Th17/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Interleucina-7/metabolismo
16.
Cell Rep ; 39(8): 110852, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35613584

RESUMO

The eye is considered immune privileged such that immune responses are dampened to protect vision. As the most anterior compartment of the eye, the cornea is exposed to pathogens and can mount immune responses that recruit effector T cells. However, presence of immune memory in the cornea is not defined. Here, we use intravital 2-photon microscopy to examine T cell responses in the cornea in mice. We show that recruitment of CD8+ T cells in response to ocular virus infection results in the formation of tissue-resident memory T (TRM) cells. Motile corneal TRM cells patrol the cornea and rapidly respond in situ to antigen rechallenge. CD103+ TRM cell generation requires antigen and transforming growth factor ß. In vivo imaging in humans also reveals highly motile cells that patrol the healthy cornea. Our study finds that TRM cells form in the cornea where they can provide local protective immunity.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Animais , Antígenos , Córnea , Células T de Memória , Camundongos
17.
Sci Immunol ; 7(67): eabj0641, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34995096

RESUMO

The spleen is a compartmentalized organ that serves as a blood filter and safeguard of systemic immune surveillance. Labyrinthine networks of fibroblastic stromal cells construct complex niches within the white pulp and red pulp that are important for tissue homeostasis and immune activation. However, the identity and roles of the global splenic fibroblastic stromal cells in homeostasis and immune responses are poorly defined. Here, we performed a cellular and molecular dissection of the splenic reticular stromal cell landscape. We found that white pulp fibroblastic reticular cells (FRCs) responded robustly during acute viral infection, but this program of gene regulation was suppressed during persistent viral infection. Single-cell transcriptomic analyses in mice revealed diverse fibroblast cell niches and unexpected heterogeneity among podoplanin-expressing cells that include glial, mesothelial, and adventitial cells in addition to FRCs. We found analogous fibroblastic stromal cell diversity in the human spleen. In addition, we identify the transcription factor SpiB as a critical regulator required to support white pulp FRC differentiation, homeostatic chemokine expression, and antiviral T cell responses. Together, our study provides a comprehensive map of fibroblastic stromal cell types in the spleen and defines roles for red and white pulp fibroblasts for splenic function and orchestration of immune responses.


Assuntos
Fibroblastos/imunologia , Homeostase/imunologia , Baço/imunologia , Células Estromais/imunologia , Animais , Diferenciação Celular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/imunologia
18.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34677611

RESUMO

Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-ß signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.


Assuntos
Diferenciação Celular/genética , Tecido Linfoide/metabolismo , Células T de Memória/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular/genética , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , RNA-Seq/métodos , Receptores de Esfingosina-1-Fosfato/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
20.
Adv Healthc Mater ; 5(8): 956-65, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-26845244

RESUMO

Synthetic materials employed for enhancing, replacing, or restoring biological functionality may be compromised by the host immune responses that they evoke. Surface modification has attracted substantial attention as a tool to modulate the host response to synthetic materials; however, how surface nanotopography combined with chemistry affects immune effector cell responses is still poorly understood. To address this open question, a unique set of model surfaces with controlled surface nanotopography in the range of 16, 38, and 68 nm has been generated. Tailored outermost surface chemistry that was amine, carboxyl, or methyl group rich has been provided. The combinations of these properties yield 12 surface types that are subject to functional assays assessing key immune effector cells, namely, primary neutrophil and macrophage responses in vitro. The data demonstrate that surface nanotopography leads to enhanced matrix metalloproteinase-9 production from primary neutrophils, and a decrease in pro-inflammatory cytokine secretion from primary macrophages. Together, these results are the first to directly compare the immunomodulatory effects of the cooperative interplay between surface nanotopography and chemistry.


Assuntos
Macrófagos/efeitos dos fármacos , Nanopartículas/química , Nanotecnologia/métodos , Neutrófilos/citologia , Ácidos/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Camundongos Endogâmicos C57BL , Microscopia de Força Atômica , Ativação de Neutrófilo , Espectroscopia Fotoeletrônica , Propriedades de Superfície
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA