RESUMO
Immunosenescence poses a significant challenge to tumor immunotherapy in elderly individuals. In this issue of Cell, Zhivaki et al. elucidate that dendritic cells "hyperactivated" by specific adjuvants elicit TH1-skewed CD4+ T cell responses in a manner contingent on the NLRP3 inflammasome, which can eliminate tumors in aged mice.
Assuntos
Células Dendríticas , Animais , Células Dendríticas/imunologia , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/imunologia , Imunoterapia/métodos , Linfócitos T CD4-Positivos/imunologia , Humanos , Envelhecimento/imunologia , Células Th1/imunologia , ImunossenescênciaRESUMO
Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.
Assuntos
Linfócitos T CD4-Positivos , Células Dendríticas , Camundongos Endogâmicos C57BL , Células Dendríticas/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Camundongos , Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Vacinas Anticâncer/imunologia , Feminino , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/metabolismo , Antígeno CTLA-4/metabolismo , Movimento Celular , Antígenos de Neoplasias/imunologiaRESUMO
Hematopoietic stem cells (HSCs) and downstream progenitors have long been studied based on phenotype, cell purification, proliferation, and transplantation into myeloablated recipients. These experiments, complemented by data on expression profiles, mouse mutants, and humans with hematopoietic defects, are the foundation for the current hematopoietic differentiation tree. However, there are fundamental gaps in our knowledge of the quantitative and qualitative operation of the HSC/progenitor system under physiological and pathological conditions in vivo. The hallmarks of HSCs, self-renewal and multipotency, are observed in in vitro assays and cell transplantation experiments; however, the extent to which these features occur naturally in HSCs and progenitors remains uncertain. We focus here on work that strives to address these unresolved questions, with emphasis on fate mapping and modeling of the hematopoietic flow from stem cells toward myeloid and lymphoid lineages during development and adult life.
Assuntos
Envelhecimento/imunologia , Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Células Progenitoras Linfoides/fisiologia , Animais , Linhagem da Célula , Autorrenovação Celular , Humanos , Camundongos , Modelos Teóricos , TranscriptomaRESUMO
The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
Assuntos
Envelhecimento , Linfócitos T CD8-Positivos , Células Dendríticas , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos , Células Dendríticas/imunologia , Envelhecimento/imunologia , Camundongos Endogâmicos C57BL , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Humanos , Neoplasias/imunologia , Linhagem Celular Tumoral , Feminino , Ativação Linfocitária/imunologiaRESUMO
Our immune system has evolved to protect us from pathogens and maintain homeostasis through localization in diverse tissue sites throughout the body. Immune responses are orchestrated by T cells, which direct pathogen clearance at the infection site and establish tissue-resident memory T cells (TRMs) for protection immunity. Here, we discuss how tissue immune responses are influenced by various stressors (e.g., metabolic, environmental, aging) that are rapidly changing due to climate fluctuations and globalization. We propose potential strategies for targeting tissue immunity to mitigate future pathogenic and environmental challenges and areas of investigation that can elucidate mechanisms for adapting and restoring homeostasis.
Assuntos
Imunidade , Especificidade de Órgãos/imunologia , Envelhecimento/imunologia , Animais , Meio Ambiente , Humanos , Sistema Imunitário/fisiologia , Linfócitos T/imunologiaRESUMO
The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.
Assuntos
Envelhecimento , Senescência Celular , Pneumopatias , Pulmão , Imunidade Adaptativa , Idoso , Envelhecimento/imunologia , Envelhecimento/patologia , COVID-19/imunologia , COVID-19/patologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Pneumopatias/imunologia , Pneumopatias/patologia , Estresse OxidativoRESUMO
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/metabolismoRESUMO
Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.
Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologiaRESUMO
For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.
Assuntos
Encéfalo/imunologia , Imunidade/fisiologia , Microglia/imunologia , Doenças Neurodegenerativas/imunologia , Envelhecimento/imunologia , Barreira Hematoencefálica/imunologia , Células da Medula Óssea/imunologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/imunologia , Humanos , Subpopulações de Linfócitos/imunologia , Macrófagos/imunologiaRESUMO
The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell-intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive-memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.
Assuntos
Envelhecimento/imunologia , Imunidade Celular , Linfócitos T/imunologia , Envelhecimento/genética , Autoimunidade/genética , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Suscetibilidade a Doenças/imunologia , Epigênese Genética/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Proteostase/genética , Proteostase/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Timo/imunologia , Timo/fisiopatologiaRESUMO
Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.
Assuntos
Tecido Adiposo/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Tecido Adiposo/citologia , Envelhecimento/imunologia , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , PPAR gama/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologiaRESUMO
Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.
Assuntos
Doenças Transmissíveis , Humanos , Fatores Etários , Doenças Transmissíveis/mortalidade , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/epidemiologia , Imunidade Adaptativa/genética , Envelhecimento/imunologia , Envelhecimento/genética , PandemiasAssuntos
Envelhecimento , Doença de Alzheimer , Imunidade Inata , Receptor Gatilho 1 Expresso em Células Mieloides , Doença de Alzheimer/imunologia , Humanos , Envelhecimento/imunologia , Animais , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , CamundongosRESUMO
Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.
Assuntos
Dietoterapia , Imunidade , Envelhecimento/imunologia , Restrição Calórica , Humanos , Inflamação , Corpos Cetônicos/biossíntese , Corpos Cetônicos/imunologia , Desnutrição/imunologia , Microbiota/imunologia , Fenômenos Fisiológicos da Nutrição/imunologiaRESUMO
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Ativação do Complemento , Complemento C1q/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Microglia/metabolismo , Envelhecimento/imunologia , Animais , Líquido Cefalorraquidiano , Complemento C1q/genética , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Granulinas , Humanos , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Lisossomos/metabolismo , Redes e Vias Metabólicas , Camundongos , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/metabolismo , Progranulinas , Sinapses/metabolismo , Tálamo/metabolismoRESUMO
Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.
Assuntos
Imunidade Adaptativa/imunologia , Envelhecimento/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Animais , Senescência Celular/imunologia , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.
Assuntos
Envelhecimento/imunologia , Transporte Biológico/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Animais , Quimiocina CXCL1/imunologia , Células Endoteliais/imunologia , Endotélio Vascular/imunologia , Feminino , Junções Intercelulares/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-8B/imunologia , Vênulas/imunologiaRESUMO
Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4+ T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4+ T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4+ T cells that potentiates aging-related autoimmunity.
Assuntos
Envelhecimento/imunologia , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Citoplasma/imunologia , Proteína Quinase Ativada por DNA/imunologia , DNA/imunologia , Inflamação/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/imunologia , Proliferação de Células/fisiologia , Reparo do DNA/imunologia , Células HEK293 , Humanos , Células Jurkat , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células U937RESUMO
Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.