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Key Points A decline in T-cell immunity is one of the most consistent and most profound deficiencies of the elderly. Therapeutic correction of this decline often restores immune responsiveness and immune defence. T-cell immune decline in the elderly has at least two underpinnings: a drop in the responsiveness of naive T cells to stimulation (cell-autonomous defects) and a reduction in naive T-cell numbers and diversity that leads to a dominant memory T-cell pool (T-cell population imbalance). This article discusses two key causes of age-related T-cell population imbalance: homeostatic cycling or proliferative expansion in the peripheral T-cell pool, and latent persistent infections, which repeatedly stimulate the T-cell pool over the lifetime of the individual. The reduction in production of naive T cells by the thymus forces the ageing organism to rely on compensatory homeostatic mechanisms to maintain the balance between naive and memory T-cell pools. Although this may be initially successful, recent evidence suggests that late in life these mechanisms exhaust their usefulness and actually contribute to a further demise of the remaining naive T cells. Latent persistent infections, particularly with herpesviruses, lead to life-long periodic restimulation of the immune system, here, evidence is presented for the role of viral reactivation in this restimulation using a mouse model of herpesvirus infection and ageing. Relative roles and the interplay between the homeostatic and viral factors are discussed, with the former having a surprisingly prominent role. Finally, modes of immune rejuvenation and anti-ageing intervention are debated in light of these advances in our knowledge. A decline in T-cell immunity is a major cause of morbidity and mortality from infectious diseases in the elderly. Janko Nikolich-Žugich weighs up the relative roles of and the interplay between homeostatic factors and persistent viruses in immune senescence. A diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.

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. Nikolich-Žugich reviews recent developments in our understanding of age-related changes affecting key components of immunity

The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a nonreactivating, latent-like or a replicative infection in CD34⁺ hematopoietic progenitor cells, we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides insight into the HCMV transcriptome associated with latency in the host and a resource for investigating virus–host interactions underlying persistence.

Major histocompatibility complex (mhc)-encoded molecules govern immune responses by presenting antigenic peptides to T cells. The extensive polymorphism of genes encoding these molecules is believed to enhance immune defense by broadening the array of antigenic peptides available for T cell recognition, but direct evidence supporting the importance of this mechanism in combating pathogens is limited. Here we link mhc polymorphism-driven diversification of the cytotoxic T lymphocyte (CTL) repertoire to the generation of high-avidity, protective antiviral T cells and to superior antiviral defense. Thus, much of the beneficial effect of the mhc polymorphism in immune defense may be due to its critical influence on the properties of the selected CTL repertoire.

In the version of this Review initially published, the type of cell in the final sentence of the legend to Figure 3 (group 2 innate lymphoid cells) was incorrect. The correct type of cell is group 3 innate lymphoid cells. The error has been corrected in the HTML and PDF versions of the article.

In the version of this article initially published, the year of birth provided (1960) was incorrect. The correct year is 1961. The error has been corrected in the HTML and PDF versions of the article.

Key Points Intense investigation has elucidated the molecular mechanisms that generate the structural diversity of the T-cell receptor (TCR) repertoire. The first reliable estimates of actual TCR diversity were recently published, however, the biological impact of TCR diversity is still being investigated. Potential TCR diversity, which is in the order of 1 × 10 15 before thymic selection, and 1 × 10 13 after thymic selection, stands in sharp contrast with the estimated actual, expressed diversity in a given organism at a given time point — 2 × 10 6 in mice and 2 × 10 7 in humans. This limit is imposed in part by the fact that there are fewer T cells in the body than there are potential TCR molecules. However, the potential of ∼1 × 10 13 TCRs is used, but in different organisms over time. It was shown that even genetically identical animals express highly diverse TCR repertoires, with as little as 20% overlap between them. Structural TCR diversity is broadened by TCR crossreactivity — the propensity of a TCR to react with more than one peptide–MHC (pMHC) ligand. However, sharp differences exist in our estimates of TCR crossreactivity (some authors estimate that a single TCR might recognize more than 1 × 10 6 pMHC ligands) and in the threshold at which this crossreactivity becomes important in pathogen resistance. T cells also show functional diversification (that is, the ability to mobilize distinct effector and regulatory functions) and this diversity is probably important for combating pathogens. T-cell diversity contributes to immune defence in two ways: it provides an initial pool from which the best and most efficient T cells will be selected to attack the pathogen; and it provides the flexible TCR reserve should the pathogen attempt to escape by mutation. Evidence from models with experimental or spontaneous restrictions in TCR diversity shows that in most models, even modest reductions in structural diversity tend to result in impaired responses to antigens and pathogens. This indicates that in most cases, TCR crossreactivity cannot compensate for the loss of structural diversity, indicating that the biological relevance of TCR crossreactivity for pathogen resistance is rather limited. There is a natural reduction in TCR diversity on aging and a pathophysiological reduction in TCR diversity after infection with HIV/highly active antiretroviral therapy and after bone-marrow transplantation. These conditions represent outstanding (and clinically relevant) models to further investigate the in vivo relevance of a broad TCR repertoire and functional T-cell diversification. A given combination of T-cell structural and functional diversity and T-cell precursor numbers will probably prove to be crucial for successful pathogen resistance, and TCR crossreactivity could also have a role. The challenge is to use incisive methods to uncover this balance and dissect its precise components, to achieve optimal protective responses by vaccination and immune modulation. In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-αβ gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response.

Summary Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNF[alpha], IL-6, IL-1[beta], IFN[alpha], IFN[gamma], CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections.

Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3(-/-)×Irf7(-/-) double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3(-/-)×Irf5(-/-)×Irf7(-/-) triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar(-/-)). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar(-/-) mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs(-/-) mDC. The relative equivalence of TKO and Mavs(-/-) responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors ( n  = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer ( n  = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy. After two doses of the BNT162b2 vaccine, virus-specific antibodies and T cells were reduced in patients with solid tumors as compared to individuals without cancer, but neutralizing antibodies increased in most patients who received a third vaccine dose.