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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800867

RESUMO

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.


Assuntos
Envelhecimento/imunologia , Células Apresentadoras de Antígenos/imunologia , Subpopulações de Linfócitos B/imunologia , Mitocôndrias/fisiologia , Regeneração/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Citocinas/fisiologia , DNA/metabolismo , DNA Mitocondrial/metabolismo , Reposicionamento de Medicamentos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Homeostase , Humanos , Imunidade Inata , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Imunologia de Transplantes , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/fisiopatologia
2.
Cell ; 184(6): 1401, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33740443

RESUMO

The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74,000 participants (half receiving placebo) after intramuscular delivery of two shots, 3-4 weeks apart. To view this Bench to Bedside, open or download the PDF.


Assuntos
/imunologia , /imunologia , /imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêutico , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lipossomos , Nanopartículas , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Resultado do Tratamento
3.
Sci Rep ; 11(1): 5402, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686135

RESUMO

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Assuntos
Sistema Nervoso Central/patologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Taurina/análogos & derivados , Animais , Apresentação do Antígeno/efeitos dos fármacos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Proliferação de Células/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Recidiva , Baço/patologia , Linfócitos T/efeitos dos fármacos , Taurina/farmacologia , Ácido gama-Aminobutírico/farmacologia
4.
ACS Appl Mater Interfaces ; 13(7): 7913-7923, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33573372

RESUMO

Biomimetic biomaterials are being actively explored in the context of cancer immunotherapy because of their ability to directly engage the immune system to generate antitumor responses. Unlike cellular therapies, biomaterial-based immunotherapies can be precisely engineered to exhibit defined characteristics including biodegradability, physical size, and tuned surface presentation of immunomodulatory signals. In particular, modulating the interface between the biomaterial surface and the target biological cell is key to enabling biological functions. Synthetic artificial antigen presenting cells (aAPCs) are promising as a cancer immunotherapy but are limited in clinical translation by the requirement of ex vivo cell manipulation and adoptive transfer of antigen-specific CD8+ T cells. To move toward acellular aAPC technology for in vivo use, we combine poly(lactic-co-glycolic acid) (PLGA) and cationic poly(beta-amino-ester) (PBAE) to form a biodegradable blend based on the hypothesis that therapeutic aAPCs fabricated from a cationic blend may have improved functions. PLGA/PBAE aAPCs demonstrate enhanced surface interactions with antigen-specific CD8+ T cells that increase T cell activation and expansion ex vivo, associated with significantly increased conjugation efficiency of T cell stimulatory signals to the aAPCs. Critically, these PLGA/PBAE aAPCs also expand antigen-specific cytotoxic CD8+ T cells in vivo without the need of adoptive transfer. Treatment with PLGA/PBAE aAPCs in combination with checkpoint therapy decreases tumor growth and extends survival in a B16-F10 melanoma mouse model. These results demonstrate the potential of PLGA/PBAE aAPCs as a biocompatible, directly injectable acellular therapy for cancer immunotherapy.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Artificiais/imunologia , Imunoterapia , Melanoma/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Polímeros/química , Animais , Células Artificiais/química , Linfócitos T CD8-Positivos/imunologia , Cátions/química , Cátions/imunologia , Melanoma/imunologia , Camundongos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Propriedades de Superfície
5.
Cells ; 10(2)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33514016

RESUMO

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucócitos Mononucleares/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Humanos , Testes Imunológicos/métodos , Peptídeos/imunologia
6.
Mol Immunol ; 130: 1-6, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340930

RESUMO

The capacity of α-galactosylceramide (α-GalCer) to act as an anti-cancer agent in mice through the specific stimulation of type I NKT (iNKT) cells has prompted extensive investigation to translate this finding to the clinic. However, low frequencies of iNKT cells in cancer patients and their hypo-responsiveness to repeated stimulation have been seen as barriers to its efficacy. Currently the most promising clinical application of α-GalCer, or its derivatives, is as stimuli for ex vivo expansion of iNKT cells for adoptive therapy, although some encouraging clinical results have recently been reported using α-GalCer pulsed onto large numbers of antigen presenting cells (APCs). In on-going preclinical studies, attempts to improve efficacy of injected iNKT cell agonists have focussed on optimising presentation in vivo, through encapsulation in particulate vectors, making structural changes that help binding to the presenting molecule CD1d, or injecting agonists covalently attached to recombinant CD1d. Variations on these same approaches are being used to enhance the APC-licencing function of iNKT cells in vivo to induce adaptive immune responses to associated tumour antigens. Looking ahead, a unique capacity of in vivo-activated iNKT cells to facilitate formation of resident memory CD8+ T cells is a new observation that could find a role in cancer therapy.


Assuntos
Galactosilceramidas/uso terapêutico , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Células T Matadoras Naturais/efeitos dos fármacos , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Galactosilceramidas/farmacologia , Humanos , Ativação Linfocitária/fisiologia , Células T Matadoras Naturais/fisiologia , Células T Matadoras Naturais/transplante , Neoplasias/imunologia
7.
Methods Mol Biol ; 2183: 1-8, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32959236

RESUMO

In this opening chapter, we outline the basics of vaccine delivery and subsequent immune reactivity. Vaccine delivery is an augmentation to immunization more generally in that a delivery reagent is harnessed to improve administration of the key ingredient (i.e., the antigen) needed to provoke an immune response. In this chapter, we discuss the evolution of vaccine design and how such efforts evolved into targeted administration/delivery of key antigens. We then provide overview descriptions of vaccine immune responses and methods for assessment. More generally, the chapter sets the tone for the remainder of this book, which will focus upon each step of the vaccine process with a special emphasis on how vaccine delivery contributes to overall health outcomes.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade , Vacinação , Vacinas/administração & dosagem , Vacinas/imunologia , Adjuvantes Imunológicos , Animais , Apresentação do Antígeno , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Vacinação/métodos
8.
Elife ; 92020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33346730

RESUMO

When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome toward the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict mirotubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.


Assuntos
Centrossomo/metabolismo , Cinesina/metabolismo , Microtúbulos/metabolismo , Linfócitos T/imunologia , Actinas/metabolismo , Células Apresentadoras de Antígenos/imunologia , Citoesqueleto/metabolismo , Humanos , Sinapses Imunológicas/metabolismo , Ativação Linfocitária
9.
Vaccine ; 38(48): 7629-7637, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33071000

RESUMO

This work demonstrates the presence of immune regulatory cells in the cervical lymph nodes draining Bacillus Calmette-Guérin (BCG) vaccinated site on the dorsum of the ear in guinea pigs. It is shown that whole cervical lymph node cells did not proliferate in vitro in the presence of soluble mycobacterial antigens (PPD or leprosin) despite being responsive to whole mycobacteria. Besides, T cells from these lymph nodes separated as a non-adherent fraction on a nylon wool column, proliferated to PPD in the presence of autologous antigen presenting cells. Interestingly, addition of as low as 20% nylon wool adherent cells to these, sharply decreased the proliferation by 83%. Looking into what cells in the adherent fraction suppressed the proliferation, it was found that neither the T cell nor the macrophage enriched cell fractions of this population individually showed suppressive effect, indicating that their co-presence was necessary for the suppression. Since BCG induced granulomas resolve much faster than granulomas induced by other mycobacteria such as Mycobacterium leprae the present experimental findings add to the existing evidence that intradermal BCG vaccination influences subsequent immune responses in the host and may further stress upon its beneficial role seen in Covid-19 patients.


Assuntos
Antígenos de Bactérias/farmacologia , Vacina BCG/farmacologia , Granuloma/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Tuberculina/farmacologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/microbiologia , Adesão Celular , Proliferação de Células , Infecções por Coronavirus/prevenção & controle , Orelha , Feminino , Granuloma/microbiologia , Cobaias , Humanos , Injeções Intradérmicas , Linfonodos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Mycobacterium bovis/imunologia , Mycobacterium leprae/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Remissão Espontânea , Linfócitos T/classificação , Linfócitos T/efeitos dos fármacos , Linfócitos T/microbiologia
10.
Front Immunol ; 11: 559113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072098

RESUMO

As the recent outbreak of SARS-CoV-2 has highlighted, the threat of a pandemic event from zoonotic viruses, such as the deadly influenza A/H7N9 virus subtype, continues to be a major global health concern. H7N9 virus strains appear to exhibit greater disease severity in mammalian hosts compared to natural avian hosts, though the exact mechanisms underlying this are somewhat unclear. Knowledge of the H7N9 host-pathogen interactions have mainly been constrained to natural sporadic human infections. To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. Intriguingly, we observed variable disease outcomes when ferrets were inoculated with the A/Anhui/1/2013 (H7N9) strain. We observed relatively reduced antigen-presenting cell activation in lymphoid tissues which may be correlative with increased disease severity. Additionally, depletions in CD8+ T cells were not apparent in sick animals. This study provides further insight into the ways that lymphocytes maturate and traffic in response to H7N9 infection in the ferret model.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/imunologia , Animais , Células Apresentadoras de Antígenos/patologia , Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Furões , Humanos , Infecções por Orthomyxoviridae/patologia , Pandemias , Pneumonia Viral/imunologia
11.
PLoS One ; 15(9): e0238819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976541

RESUMO

Adoptive cell transfer of Chimeric Antigen Receptor (CAR)-T cells showed promising results in patients with B cell malignancies. However, the detailed mechanism of CAR-T cell interaction with the target tumor cells is still not well understood. This work provides a systematic method for analyzing the activation and degranulation of second-generation CAR-T cells utilizing antigen-presenting cell surfaces. Antigen-presenting cell surfaces composed of circular micropatterns of CAR-specific anti-idiotype antibodies have been developed to mimic the interaction of CAR-T cells with target tumor cells using micro-contact printing. The levels of activation and degranulation of fixed non-transduced T cells (NT), CD19.CAR-T cells, and GD2.CAR-T cells on the antigen-presenting cell surfaces were quantified and compared by measuring the intensity of the CD3ζ chain phosphorylation and the Lysosome-Associated Membrane Protein 1 (LAMP-1), respectively. The size and morphology of the cells were also measured. The intracellular Ca2+ flux of NT and CAR-T cells upon engagement with the antigen-presenting cell surface was reported. Results suggest that NT and CD19.CAR-T cells have comparable activation levels, while NT have higher degranulation levels than CD19.CAR-T cells and GD2.CAR-T cells. The findings show that antigen-presenting cell surfaces allow a quantitative analysis of the molecules involved in synapse formation in different CAR-T cells in a systematic, reproducible manner.


Assuntos
Antígenos de Superfície/metabolismo , Linfoma de Células B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Transferência Adotiva/métodos , Células Apresentadoras de Antígenos/imunologia , Antígenos CD19/metabolismo , Linfócitos B/imunologia , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Linfócitos T/imunologia
12.
PLoS Pathog ; 16(9): e1008799, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32898164

RESUMO

Professional antigen-presenting cells (APCs), like macrophages (Mϕs) and dendritic cells (DCs), are central players in the induction of natural and vaccine-induced immunity to malaria, yet very little is known about the interaction of SPZ with human APCs. Intradermal delivery of whole-sporozoite vaccines reduces their effectivity, possibly due to dermal immunoregulatory effects. Therefore, understanding these interactions could prove pivotal to malaria vaccination. We investigated human APC responses to recombinant circumsporozoite protein (recCSP), SPZ and anti-CSP opsonized SPZ both in monocyte derived MoDCs and MoMϕs. Both MoDCs and MoMϕs readily took up recCSP but did not change phenotype or function upon doing so. SPZ are preferentially phagocytosed by MoMϕs instead of DCs and phagocytosis greatly increased after opsonization. Subsequently MoMϕs show increased surface marker expression of activation markers as well as tolerogenic markers such as Programmed Death-Ligand 1 (PD-L1). Additionally they show reduced motility, produce interleukin 10 and suppressed interferon gamma (IFNγ) production by antigen specific CD8+ T cells. Importantly, we investigated phenotypic responses to SPZ in primary dermal APCs isolated from human skin explants, which respond similarly to their monocyte-derived counterparts. These findings are a first step in enhancing our understanding of pre-erythrocytic natural immunity and the pitfalls of intradermal vaccination-induced immunity.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Macrófagos/imunologia , Malária/imunologia , Plasmodium berghei/imunologia , Proteínas de Protozoários/imunologia , Pele/imunologia , Esporozoítos/imunologia , Animais , Células Cultivadas , Feminino , Humanos , Macrófagos/parasitologia , Malária/parasitologia , Camundongos , Pele/parasitologia
13.
Int J Nanomedicine ; 15: 5527-5543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848386

RESUMO

Background: Poly(lactic-co-glycolic acid) (PLGA) has been extensively applied for sustained drug delivery and vaccine delivery system. However, vaccines delivered by PLGA nanoparticles alone could not effectively activate antigen-presenting cells (APCs) to induce strong immune responses. Purpose: The aim of the present study was to design polyethylenimine (PEI)-modified Chinese yam polysaccharide (CYP)-encapsulated PLGA nanoparticles (CYPP-PEI) as a vaccine delivery system and evaluate the adjuvant activities in vitro and in vivo. Materials and Methods: Cationic-modified nanoparticles exhibited high antigen absorption and could be efficiently taken by APCs to enhance the immune responses. Therefore, PEI-modified CYP-encapsulated PLGA nanoparticles (CYPP-PEI) were prepared. The storage stability and effective adsorption capacity for porcine circovirus-2 (PCV-2) antigen of these antigen-absorbed nanoparticles were measured for one month. Furthermore, the adjuvant activity of CYPP-PEI nanoparticles was evaluated on macrophages in vitro and through immune responses triggered by PCV-2 antigen in vivo. Results: The PCV-2 absorbed CYPP-PEI nanoparticles showed excellent storage stability and high absorption efficiency of PCV-2 antigen. In vitro, CYPP-PEI nanoparticles promoted antigen uptake, enhanced surface molecular expressions of CD80 and CD86, and improved cytokine secretion of TNF-α, IFN-γ, and IL-12p70 in macrophages. After immunization with CYPP-PEI/PCV-2 formulation in mice, the expressions of surface activation markers on dendritic cells which located in draining lymph nodes were increased, such as MHCI, MHCII, and CD80. In addition, CYPP-PEI nanoparticles induced dramatically high PCV-2-specific IgG levels which could last for a long time and stimulated the secretion of subtype antibodies and cytokines. The results showed that CYPP-PEI could induce Th1/Th2 mixed but Th1-biased type immune responses. Conclusion: Polyethylenimine-modified Chinese yam polysaccharide-encapsulated PLGA nanoparticle was a potential vaccine delivery system to trigger strong and persistent immune responses.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Dioscorea/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polissacarídeos/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Antígenos/farmacologia , Circovirus/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Estabilidade de Medicamentos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos ICR , Nanopartículas/administração & dosagem , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Vacinas/administração & dosagem , Vacinas/imunologia
14.
Nat Commun ; 11(1): 3734, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709894

RESUMO

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαß+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.


Assuntos
Antígenos/imunologia , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/metabolismo , Infecções Bacterianas , Medula Óssea , Linhagem Celular Tumoral , Feminino , Tolerância Imunológica , Linfonodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/metabolismo , Timócitos/imunologia , Fatores de Transcrição/genética
15.
Nature ; 585(7826): 591-596, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526765

RESUMO

Recent clinical and experimental evidence has evoked the concept of the gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1-4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.


Assuntos
Encéfalo/citologia , Intestinos/citologia , Intestinos/inervação , Fígado/citologia , Fígado/inervação , Neurônios/fisiologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Vias Aferentes , Animais , Células Apresentadoras de Antígenos/imunologia , Colite/imunologia , Colite/metabolismo , Colite/patologia , Homeostase , Humanos , Intestinos/imunologia , Masculino , Camundongos , Ratos , Receptores Muscarínicos/metabolismo , Baço/citologia , Baço/imunologia , Nervo Vago/fisiologia
16.
Nat Commun ; 11(1): 2739, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483165

RESUMO

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.


Assuntos
Escherichia coli/imunologia , Imunoterapia/métodos , Proteínas de Membrana/imunologia , Neoplasias/terapia , Transdução de Sinais/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Linhagem Celular Tumoral , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Genética/métodos , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Neoplasias/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Transdução de Sinais/genética , Biologia Sintética/métodos , Biologia Sintética/tendências
17.
Nat Med ; 26(7): 1125-1134, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451499

RESUMO

Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.


Assuntos
Infecções Bacterianas/imunologia , Neoplasias da Mama/imunologia , Melanoma Experimental/imunologia , Microambiente Tumoral/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Ativação Linfocitária/imunologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Linfócitos T/imunologia , Microambiente Tumoral/genética
18.
Mol Immunol ; 123: 64-73, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422416

RESUMO

T cells can help confer protective immunity by eliminating infections and tumors or drive immunopathology by damaging host cells. Both outcomes require a series of steps from the activation of naïve T cells to their clonal expansion, differentiation and migration to tissue sites. In addition to specific recognition of the antigen via the T cell receptor (TCR), multiple accessory signals from costimulatory molecules, cytokines and metabolites also influence each step along the progression of the T cell response. Current efforts to modify effector T cell function in many clinical contexts focus on the latter - which encompass antigen-independent and broad, contextual regulators. Not surprisingly, such approaches are often accompanied by adverse events, as they also affect T cells not relevant to the specific treatment. In contrast, fine tuning T cell responses by precisely targeting antigen-specific TCR signals has the potential to radically alter therapeutic strategies in a focused manner. Development of such approaches, however, requires a better understanding of functioning of the TCR and the biochemical signaling network coupled to it. In this article, we review some of the recent advances which highlight important roles of TCR signals throughout the activation and differentiation of T cells during an immune response. We discuss how, an appreciation of specific signaling modalities and variant ligands that influence the function of the TCR has the potential to influence design principles for the next generation of pharmacologic and cellular therapies, especially in the context of tumor immunotherapies involving adoptive cell transfers.


Assuntos
Transferência Adotiva/métodos , Imunidade Celular/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular/imunologia , Humanos , Imunoterapia/métodos , Ativação Linfocitária , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais/imunologia
19.
Nat Commun ; 11(1): 2049, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341343

RESUMO

ILCs and T helper cells have been shown to exert bi-directional regulation in mice. However, how crosstalk between ILCs and CD4+ T cells influences immune function in humans is unknown. Here we show that human intestinal ILCs co-localize with T cells in healthy and colorectal cancer tissue and display elevated HLA-DR expression in tumor and tumor-adjacent areas. Although mostly lacking co-stimulatory molecules ex vivo, intestinal and peripheral blood (PB) ILCs acquire antigen-presenting characteristics triggered by inflammasome-associated cytokines IL-1ß and IL-18. IL-1ß drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-κB-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4+ T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-ß. Our results suggest that circulating and tissue-resident ILCs have the intrinsic capacity to respond to the immediate cytokine milieu and regulate local CD4+ T-cell responses, with potential implications for anti-tumor immunity and inflammation.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Citocinas/imunologia , Imunidade Inata , Linfócitos/imunologia , Animais , Apresentação do Antígeno , Linfócitos T CD4-Positivos/imunologia , Neoplasias do Colo/imunologia , Humanos , Inflamassomos/imunologia , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leucócitos Mononucleares/imunologia , Camundongos
20.
Nat Commun ; 11(1): 1794, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286285

RESUMO

Although group 3 innate lymphoid cells (ILC3s) are efficient inducers of T cell responses in the spleen, they fail to induce CD4+ T cell proliferation in the gut. The signals regulating ILC3-T cell responses remain unknown. Here, we show that transcripts associated with MHC II antigen presentation are down-modulated in intestinal natural cytotoxicity receptor (NCR)- ILC3s. Further data implicate microbiota-induced IL-23 as a crucial signal for reversible silencing of MHC II in ILC3s, thereby reducing the capacity of ILC3s to present antigen to T cells in the intestinal mucosa. Moreover, IL-23-mediated MHC II suppression is dependent on mTORC1 and STAT3 phosphorylation in NCR- ILC3s. By contrast, splenic interferon-γ induces MHC II expression and CD4+ T cell stimulation by NCR- ILC3s. Our results thus identify biological circuits for tissue-specific regulation of ILC3-dependent T cell responses. These pathways may have implications for inducing or silencing T cell responses in human diseases.


Assuntos
Apresentação do Antígeno/imunologia , Imunidade Inata , Linfócitos/imunologia , Microbiota , Baço/citologia , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/metabolismo , Polaridade Celular , Regulação para Baixo , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/metabolismo , Interleucina-23/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Microbiota/genética , Microbiota/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Fosforilação , Análise de Componente Principal , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/imunologia , Transativadores/genética , Transativadores/metabolismo , Transcrição Genética
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