Nuclear Sirtuins and the Aging of the Immune System

The immune system undergoes major changes with age that result in altered immune populations, persistent inflammation, and a reduced ability to mount effective immune responses against pathogens and cancer cells. Aging-associated changes in the immune system are connected to other age-related diseases, suggesting that immune system rejuvenation may provide a feasible route to improving overall health in the elderly. The Sir2 family of proteins, also called sirtuins, have been broadly implicated in genome homeostasis, cellular metabolism, and aging. Sirtuins are key responders to cellular and environmental stress and, in the case of the nuclear sirtuins, they do so by directing responses to chromatin that include gene expression regulation, retrotransposon repression, enhanced DNA damage repair, and faithful chromosome segregation. In the immune system, sirtuins instruct cellular differentiation from hematopoietic precursors and promote leukocyte polarization and activation. In hematopoietic stem cells, sirtuins safeguard quiescence and stemness to prevent cellular exhaustion. Regulation of cytokine production, which, in many cases, requires NF-κB regulation, is the best-characterized mechanism by which sirtuins control innate immune reactivity. In adaptive immunity, sirtuins promote T cell subset differentiation by controlling master regulators, thereby ensuring an optimal balance of helper (Th) T cell-dependent responses. Sirtuins are very important for immune regulation, but the means by which they regulate immunosenescence are not well understood. This review provides an integrative overview of the changes associated with immune system aging and its potential relationship with the roles of nuclear sirtuins in immune cells and overall organismal aging. Given the anti-aging properties of sirtuins, understanding how they contribute to immune responses is of vital importance and may help us develop novel strategies to improve immune performance in the aging organism.

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Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

10.2310/im.1328 ◽

2016 ◽

Author(s):

Steven K. Lundy ◽

Alison Gizinski ◽

David A. Fox

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Immune Responses ◽

Autoimmune Diseases ◽

Adaptive Immunity ◽

Cell Populations ◽

Hematopoietic Stem ◽

Innate And Adaptive Immunity ◽

Adaptive Immune

The immune system is a complex network of cells and mediators that must balance the task of protecting the host from invasive threats. From a clinical perspective, many diseases and conditions have an obvious link to improper functioning of the immune system, and insufficient immune responses can lead to uncontrolled acute and chronic infections. The immune system may also be important in tumor surveillance and control, cardiovascular disease, health complications related to obesity, neuromuscular diseases, depression, and dementia. Thus, a working knowledge of the role of immunity in disease processes is becoming increasingly important in almost all aspects of clinical practice. This review provides an overview of the immune response and discusses immune cell populations and major branches of immunity, compartmentalization and specialized immune niches, antigen recognition in innate and adaptive immunity, immune tolerance toward self antigens, inflammation and innate immune responses, adaptive immune responses and helper T (Th) cell subsets, components of the immune response that are important targets of treatment in autoimmune diseases, mechanisms of action of biologics used to treat autoimmune diseases and their approved uses, and mechanisms of other drugs commonly used in the treatment of autoimmune diseases. Figures show the development of erythrocytes, platelets, lymphocytes, and other immune system cells originating from hematopoietic stem cells that first reside in the fetal liver and later migrate to the bone marrow, antigen–major histocompatibility complex recognition by T cell receptor control of T cell survival and activation, and Th cells as central determinants of the adaptive immune response toward different stimuli. Tables list cell populations involved in innate and adaptive immunity, pattern recognition receptors with known ligands, autoantibody-mediated human diseases: examples of pathogenic mechanisms, selected Food and Drug Administration–approved autoimmune disease indications for biologics, and mechanism of action of biologics used to treat autoimmune diseases. This review contains 3 highly rendered figures, 5 tables, and 64 references.

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Causes and Mechanisms of Hematopoietic Stem Cell Aging

International Journal of Molecular Sciences ◽

10.3390/ijms20061272 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1272 ◽

Cited By ~ 10

Author(s):

Jungwoon Lee ◽

Suk Yoon ◽

Inpyo Choi ◽

Haiyoung Jung

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

The Elderly ◽

Cell Aging ◽

Extrinsic Factors ◽

Hematopoietic Stem ◽

Age Related ◽

Stem Cell Aging ◽

Related Stress

Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging.

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Assessment of Lymph Node Stromal Cells as an Underlying Factor in Age-Related Immune Impairment

The Journals of Gerontology Series A ◽

10.1093/gerona/glz029 ◽

2019 ◽

Vol 74 (11) ◽

pp. 1734-1743 ◽

Cited By ~ 7

Author(s):

April R Masters ◽

Alexxus Hall ◽

Jenna M Bartley ◽

Spencer R Keilich ◽

Erica C Lorenzo ◽

...

Keyword(s):

T Cells ◽

Steady State ◽

Immune Responses ◽

Stromal Cells ◽

Stromal Cell ◽

Influenza Infection ◽

Cell Subset ◽

The Elderly ◽

Age Related ◽

The Impact

Abstract Aging negatively impacts immunity, resulting in inefficient responses to vaccinations and infections. Fibroblastic reticular cells (FRCs) are the major stromal cell subset in lymph nodes (LNs) and play an intricate role in the orchestration and control of adaptive immune responses. Although stromal cells have a major impact on immune responses, the impact of aging on LN stromal cells remains unclear. Quantitative analysis of LN stromal cells by flow cytometry revealed that there are no significant differences in the number of stromal cells in young and aged LN at steady state but after influenza infection aged FRCs have delayed expansion as a result of reduced proliferation. Aged LNs also produce reduced levels of homeostatic chemokines, which correlates with reduced homing of naive T cells. Image analysis reveals that young and aged T-cell zone FRCs have similar morphology at steady state and after infection. Furthermore, aged FRCs did not appear to be a contributing factor in the reduced proliferation of young T cells transferred into aged LNs after influenza infection. These results demonstrate that aging alters LN stromal cell response to challenge and these age-related changes may be an underlying contributor to impaired immune responses in the elderly people.

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Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

10.2310/neuro.1328 ◽

2016 ◽

Author(s):

Steven K. Lundy ◽

Alison Gizinski ◽

David A. Fox

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Immune Responses ◽

Autoimmune Diseases ◽

Adaptive Immunity ◽

Cell Populations ◽

Hematopoietic Stem ◽

Innate And Adaptive Immunity ◽

Adaptive Immune

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Rescuing Immunosenescence via Non-Specific Vaccination

Immuno ◽

10.3390/immuno1030015 ◽

2021 ◽

Vol 1 (3) ◽

pp. 231-239

Author(s):

Alexander I. Mosa

Keyword(s):

Immune Responses ◽

The Elderly ◽

Short Review ◽

Functional Markers ◽

Healthy Life ◽

Related Disease ◽

Age Related ◽

Population Vulnerability ◽

Mechanistic Basis ◽

Promising Avenue

Discrepancies in lifespan and healthy-life span are predisposing populations to an increasing burden of age-related disease. Accumulating evidence implicates aging of the immune system, termed immunosenescence, in the pathogenesis of multiple age-related diseases. Moreover, immune dysregulation in the elderly increases vulnerability to infection and dampens pathogen-specific immune responses following vaccination. The health challenges manifesting from these age related deficits have been dramatically exemplified by the current SARS-CoV-2 pandemic. Approaches to either attenuate or reverse functional markers of immunosenescence are therefore urgently needed. Recent evidence suggests systemic immunomodulation via non-specific vaccination with live-attenuated vaccines may be a promising avenue to at least reduce aged population vulnerability to viral infection. This short review describes current understanding of immunosenescence, the historical and mechanistic basis of vaccine-mediated immunomodulation, and the outstanding questions and challenges required for broad adoption.

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Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.640224 ◽

2021 ◽

Vol 9 ◽

Author(s):

Runzi Sun ◽

Yixian Wu ◽

Huijun Zhou ◽

Yanshi Wu ◽

Zhongzhou Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Critical Role ◽

Cell Subset ◽

Tumor Immunotherapy ◽

Genetic Circuit ◽

Durable Response ◽

T Cell Immune Responses ◽

Deficient Mice

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

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Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103730118 ◽

2021 ◽

Vol 118 (23) ◽

pp. e2103730118

Author(s):

Yuka Nakajima ◽

Kenji Chamoto ◽

Takuma Oura ◽

Tasuku Honjo

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Critical Role ◽

Cell Subset ◽

Effector Memory ◽

T Cell Subset ◽

Aged Mice ◽

Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

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Immune system changes and immunosenescence

Oxford Textbook of Geriatric Medicine ◽

10.1093/med/9780198701590.003.0045 ◽

2017 ◽

pp. 331-336

Author(s):

Graham Pawelec ◽

Ludmila Müller ◽

Tamas Fülöp ◽

Deborah Dunn-Walters

Keyword(s):

Immune System ◽

Immune Responses ◽

Older People ◽

Protective Immunity ◽

Elderly Population ◽

Immune Status ◽

The Elderly ◽

Degenerative Diseases ◽

System Changes ◽

Increased Susceptibility

The immune system defends against infection, but older people paradoxically suffer not only from failing immunity resulting in increased susceptibility to infections and decreased responsiveness to vaccination, but at the same time increased inflammation and immunopathology accompanying immune responses. Interventions to reduce such deleterious effects while enhancing protective immunity are challenging but need to be confronted if we are to deal successfully with the increasing numbers of elderly and frail people in modern societies. To do this, we need to understand the mechanisms responsible for age-associated increased susceptibility to infections and immune-influenced chronic degenerative diseases of ageing. Defining relevant age-associated alterations and identifying reliable biomarkers for monitoring clinically-relevant immune status in the elderly population is crucial to overcoming these problems. Here, we briefly outline age-associated changes to immunity collectively termed ‘immunosenescence’.

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CD4 T Helper Cell Subsets and Related Human Immunological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21218011 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8011 ◽

Cited By ~ 1

Author(s):

Xiaoliang Zhu ◽

Jinfang Zhu

Keyword(s):

Transcription Factor ◽

Immune System ◽

Immune Responses ◽

Critical Role ◽

Cell Subset ◽

Lymphoid Cells ◽

T Helper Cell ◽

Helper Cell ◽

Th2 Cells ◽

T Helper

The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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Conjugate-like immunogens produced as protein capsular matrix vaccines

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1425005112 ◽

2015 ◽

Vol 112 (10) ◽

pp. E1143-E1151 ◽

Cited By ~ 19

Author(s):

Ann Thanawastien ◽

Robert T. Cartee ◽

Thomas J. Griffin ◽

Kevin P. Killeen ◽

John J. Mekalanos

Keyword(s):

T Cell ◽

Immune Responses ◽

Protective Immunity ◽

The Elderly ◽

Covalent Attachment ◽

Carrier Protein ◽

Elderly Age ◽

Conjugate Vaccines ◽

Age Cohorts ◽

Polysaccharide Antigens

Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell–independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a “carrier protein” antigen. Such “conjugate vaccines” efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines.

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