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1.
Nat Immunol ; 24(1): 96-109, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36510022

RESUMO

Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.


Assuntos
Envelhecimento , Linfócitos T CD4-Positivos , Fator de Transcrição Ikaros , Idoso , Animais , Humanos , Camundongos , Adulto Jovem , Envelhecimento/imunologia , Envelhecimento/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Montagem e Desmontagem da Cromatina , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Fator de Transcrição STAT5 , Fator de Transcrição Ikaros/metabolismo
2.
Nat Immunol ; 22(1): 10-18, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33257900

RESUMO

The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.


Assuntos
Artrite Reumatoide/imunologia , Animais , Artrite Reumatoide/etiologia , Autoimunidade , Reparo do DNA , Humanos , Inflamação/imunologia , Tolerância a Antígenos Próprios , Sinovite/imunologia , Linfócitos T/imunologia
3.
Nat Immunol ; 22(12): 1551-1562, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34811544

RESUMO

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.


Assuntos
Artrite Reumatoide/metabolismo , Ácido Aspártico/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Mitocôndrias/metabolismo , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , ADP-Ribosilação , Transferência Adotiva , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD4-Positivos/ultraestrutura , Estudos de Casos e Controles , Células Cultivadas , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Chaperona BiP do Retículo Endoplasmático/metabolismo , Feminino , Humanos , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/transplante , Mitocôndrias/ultraestrutura , Membrana Sinovial/imunologia , Membrana Sinovial/ultraestrutura , Fator de Necrose Tumoral alfa/genética
4.
Nat Immunol ; 20(3): 313-325, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718913

RESUMO

N-myristoyltransferase (NMT) attaches the fatty acid myristate to the N-terminal glycine of proteins to sort them into soluble and membrane-bound fractions. Function of the energy-sensing AMP-activated protein kinase, AMPK, is myristoylation dependent. In rheumatoid arthritis (RA), pathogenic T cells shift glucose away from adenosine tri-phosphate production toward synthetic and proliferative programs, promoting proliferation, cytokine production, and tissue invasion. We found that RA T cells had a defect in NMT1 function, which prevented AMPK activation and enabled unopposed mTORC1 signaling. Lack of the myristate lipid tail disrupted the lysosomal translocation and activation of AMPK. Instead, myristoylation-incompetent RA T cells hyperactivated the mTORC1 pathway and differentiated into pro-inflammatory TH1 and TH17 helper T cells. In vivo, NMT1 loss caused robust synovial tissue inflammation, whereas forced NMT1 overexpression rescued AMPK activation and suppressed synovitis. Thus, NMT1 has tissue-protective functions by facilitating lysosomal recruitment of AMPK and dampening mTORC1 signaling.


Assuntos
Proteínas Quinases Ativadas por AMP/imunologia , Aciltransferases/imunologia , Artrite Reumatoide/imunologia , Sinovite/imunologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Adulto , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Cultivadas , Ativação Enzimática/imunologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Interferência de RNA , Sinovite/genética , Sinovite/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
5.
Nat Immunol ; 18(9): 1025-1034, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28737753

RESUMO

Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Linfócitos T/metabolismo , Trifosfato de Adenosina/metabolismo , Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Movimento Celular/imunologia , Ácidos Graxos/biossíntese , Feminino , Perfilação da Expressão Gênica , Glicólise/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Inflamação , Masculino , Pessoa de Meia-Idade , Ácido Pirúvico/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Linfócitos T/imunologia
6.
Nature ; 610(7930): 173-181, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36171288

RESUMO

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.


Assuntos
Linfócitos T CD8-Positivos , Interleucina-2 , Receptor de Morte Celular Programada 1 , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Subunidade gama Comum de Receptores de Interleucina , Interleucina-2/imunologia , Interleucina-2/farmacologia , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2 , Subunidade beta de Receptor de Interleucina-2 , Coriomeningite Linfocítica/tratamento farmacológico , Coriomeningite Linfocítica/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fator 1 de Transcrição de Linfócitos T
7.
Semin Immunol ; 69: 101814, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37542986

RESUMO

Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Humanos , Idoso , Envelhecimento , Senescência Celular/fisiologia , Linfócitos T , Inflamação
8.
Semin Immunol ; 69: 101800, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37494738

RESUMO

The defense against infectious diseases, either through natural immunity or after vaccinations, relies on the generation and maintenance of protective T cell memory. Naïve T cells are at the center of memory T cell generation during primary responses. Upon activation, they undergo a complex, highly regulated differentiation process towards different functional states. Naïve T cells maintained into older age have undergone epigenetic adaptations that influence their fate decisions during differentiation. We review age-sensitive, molecular pathways and gene regulatory networks that bias naïve T cell differentiation towards effector cell generation at the expense of memory and Tfh cells. As a result, T cell differentiation in older adults is associated with release of bioactive waste products into the microenvironment, higher stress sensitivity as well as skewing towards pro-inflammatory signatures and shorter life spans. These maladaptations not only contribute to poor vaccine responses in older adults but also fuel a more inflammatory state.


Assuntos
Memória Imunológica , Linfócitos T , Humanos , Idoso , Diferenciação Celular , Envelhecimento , Ativação Linfocitária , Linfócitos T CD8-Positivos
9.
Immunity ; 46(3): 364-378, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28329703

RESUMO

Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Here we review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms. Processes include homeostatic proliferation that maintains compartment size at the expense of partial loss in stemness and incomplete differentiation and the activation of negative regulatory programs, which constrain effector T cell expansion and prevent increasing oligoclonality but also interfere with memory cell generation. We propose that immune failure occurs when adaptive strategies developed by the aging T cell system fail and also discuss how, in some settings, the programs associated with T cell aging culminates in a maladaptive response that directly contributes to chronic inflammatory disease.


Assuntos
Senescência Celular/imunologia , Linfócitos T/imunologia , Animais , Humanos
10.
Nat Methods ; 19(5): 547-553, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35501385

RESUMO

In this work, we describe NEAT-seq (sequencing of nuclear protein epitope abundance, chromatin accessibility and the transcriptome in single cells), enabling interrogation of regulatory mechanisms spanning the central dogma. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive T cell subsets and identify examples of TFs with regulatory activity gated by transcription, translation and regulation of chromatin binding. We also link a noncoding genome-wide association study single-nucleotide polymorphism (SNP) within a GATA motif to a putative target gene, using NEAT-seq data to internally validate SNP impact on GATA3 regulation.


Assuntos
Cromatina , Proteínas Nucleares , Cromatina/genética , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas Nucleares/genética , Transcriptoma
11.
Nat Immunol ; 14(5): 428-36, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23598398

RESUMO

In the older adult, the benefits of vaccination to prevent infectious disease are limited, mainly because of the adaptive immune system's inability to generate protective immunity. The age-dependent decrease in immunological competence, often referred to as 'immunosenescence', results from the progressive deterioration of innate and adaptive immune responses. Most insights into mechanisms of immunological aging have been derived from studies of mouse models. In this Review, we explore how well such models are applicable to understanding the aging process throughout the 80-100 years of human life and discuss recent advances in identifying and characterizing the mechanisms that underlie age-associated defective adaptive immunity in humans.


Assuntos
Envelhecimento/imunologia , Senescência Celular/imunologia , Controle de Doenças Transmissíveis , Vacinação , Vacinas/imunologia , Imunidade Adaptativa , Idoso , Idoso de 80 Anos ou mais , Animais , Humanos , Imunocompetência , Camundongos , Vacinas/administração & dosagem
12.
Immunity ; 45(4): 903-916, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27742546

RESUMO

Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4+ T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, proinflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11Alow T cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.


Assuntos
Artrite Reumatoide/imunologia , Senescência Celular/imunologia , Proteínas de Ligação a DNA/imunologia , Desoxirribonucleases/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Dano ao DNA/imunologia , Reparo do DNA/imunologia , Feminino , Humanos , Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Sinovite/imunologia , Telômero/imunologia , Regulação para Cima/imunologia
13.
Circ Res ; 132(2): 238-250, 2023 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-36656970

RESUMO

Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1+CD4+ T cells and the functional decline of NOTCH4+ T regulatory cells (Checkpoint 1). A defect in the endothelial cell barrier of adventitial vasa vasorum networks marks Checkpoint 2; the invasion of monocytes, macrophages and T cells into the arterial wall. Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). Eventually, the vascular lesions are occupied by self-renewing T cells that provide autonomy to the disease process and limit the therapeutic effectiveness of currently used immunosuppressants. The multi-step process deviating protective to pathogenic immunity offers an array of interception points that provide opportunities for the prevention and therapeutic management of this devastating autoimmune disease.


Assuntos
Arterite de Células Gigantes , Humanos , Inflamação/metabolismo , Artérias/metabolismo , Imunidade Inata , Células Gigantes/metabolismo
14.
Immunol Rev ; 294(1): 177-187, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31984519

RESUMO

In rheumatoid arthritis (RA), breakdown of self-tolerance and onset of clinical disease are separated in time and space, supporting a multi-hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease-specific metabolic signature, which enables naive CD4 T cells to differentiate into pro-inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N-myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose-6-phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.


Assuntos
Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/imunologia , Macrófagos/imunologia , Mitocôndrias/metabolismo , Animais , Artrite Reumatoide/imunologia , Autoimunidade , Dano ao DNA , Reparo do DNA , Glicólise , Humanos , Transporte Proteico
15.
Clin Exp Immunol ; 211(3): 208-223, 2023 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-36420636

RESUMO

Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses, and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system toward immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.


Assuntos
Artrite Reumatoide , Humanos , Linfócitos T , Inflamação/metabolismo , Autoimunidade , Mitocôndrias
16.
J Autoimmun ; 137: 102947, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36357240

RESUMO

Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.


Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , Idoso , Autoimunidade/fisiologia , Linfócitos T , Envelhecimento , Senescência Celular , Fatores de Risco
17.
Nature ; 552(7685): 362-367, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29236685

RESUMO

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Epigênese Genética , Memória Imunológica/imunologia , Vacina contra Febre Amarela/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA , Deutério , Perfilação da Expressão Gênica , Meia-Vida , Humanos , Memória Imunológica/genética , Contagem de Linfócitos , Camundongos , Técnica de Diluição de Radioisótopos , Transcrição Gênica , Febre Amarela/imunologia , Febre Amarela/virologia , Vírus da Febre Amarela/imunologia
18.
Proc Natl Acad Sci U S A ; 117(1): 532-540, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31879353

RESUMO

The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and ß-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α-ß pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαß dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR ß-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαß amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαß in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α-ß pairs with entire sequence identities.


Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta/genética , Gêmeos Monozigóticos/genética , Adulto , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Linfócitos T CD4-Positivos/metabolismo , Conjuntos de Dados como Assunto , Feminino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Análise de Sequência de DNA , Análise de Célula Única
20.
Proc Natl Acad Sci U S A ; 116(28): 14113-14118, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227606

RESUMO

We have recently defined a novel population of PD-1 (programmed cell death 1)+ TCF1 (T cell factor 1)+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells. Here we compared the epigenetic signature of stem-like CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of HMG (TCF) and RHD (NF-κB) transcription factor family members in contrast to higher accessibility to ETS and RUNX motifs in exhausted CD8 T cells. In addition, regulatory regions of the transcription factors Tcf7 and Id3 were more accessible in stem-like cells whereas Prdm1 and Id2 were more accessible in exhausted CD8 T cells. We also compared the epigenetic signatures of the 2 CD8 T cell subsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8 T cell subsets generated during chronic infection were strikingly different from CD8 T cell subsets from acute infection. Interestingly, the stem-like CD8 T cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells, had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T cell program represents a specific adaptation of the T cell response to persistent antigenic stimulation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Fator 1-alfa Nuclear de Hepatócito/genética , Coriomeningite Linfocítica/genética , Receptor de Morte Celular Programada 1/genética , Animais , Linfócitos T CD8-Positivos/patologia , Linhagem da Célula/imunologia , Epigênese Genética , Regulação da Expressão Gênica/imunologia , Humanos , Imunoterapia , Proteína 2 Inibidora de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
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