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Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies. Whether the immune system aging differs between men and women is barely known. Here the authors characterize gene expression, chromatin state and immune subset composition in the blood of healthy humans 22 to 93 years of age, uncovering shared as well as sex-unique alterations, and create a web resource to interactively explore the data.

Feedback regulatory circuits provided by regulatory T cells (T reg cells) and suppressive cytokines are an intrinsic part of the immune system, along with effector functions. Here we discuss some of the regulatory cytokines that have evolved to permit tolerance to components of self as well as the eradication of pathogens with minimal collateral damage to the host. Interleukin 2 (IL-2), IL-10 and transforming growth factor-β (TGF-β) are well characterized, whereas IL-27, IL-35 and IL-37 represent newcomers to the spectrum of anti-inflammatory cytokines. We also emphasize how information accumulated through in vitro as well as in vivo studies of genetically engineered mice can help in the understanding and treatment of human diseases.

Blood is the pipeline of the immune system. Assessing changes in transcript abundance in blood on a genome-wide scale affords a comprehensive view of the status of the immune system in health and disease. This review summarizes the work that has used this approach to identify therapeutic targets and biomarker signatures in the field of autoimmunity and infectious disease. Recent technological and methodological advances that will carry the blood transcriptome research field forward are also discussed.

Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISG hi ) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4 + and CD8 + T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications. Banchereau and colleagues provide a resource dataset that examines disease-related transcriptional profiles of peripheral whole-blood cells from adolescent patients with SLE by single-cell RNA-seq analysis.

Regenerative stem cell–like memory (T SCM ) CD8 + T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T SCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T SCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8 + T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8 + T cell reprogramming into T SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics. Stem cell–like memory (T SCM ) CD8 + T cells are beneficial in antitumor responses, in part due to their ability to self-renew. Khleif and colleagues demonstrate that inhibition of the kinase MEK in CD8 + T cells favors induction of T SCM and superior antitumor responses.

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 + T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27 − CD28 − CD8 + T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27 − CD28 − CD8 + T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27 − CD28 − CD8 + T cells to acquire a broad-spectrum, innate-like killing activity. Akbar and colleagues show that sestrins induce the reprogramming of non-proliferative, senescent-like CD27 – CD28 – CD8 + T cells to acquire an innate-like killing activity modulated by the NK receptor NKG2D and the adaptor molecule DAP12.

Key Points Vaccines against cancer aim to induce both tumour-specific effector T cells that can reduce the tumour mass and tumour-specific memory T cells that can control tumour relapse. Dendritic cells (DCs) induce and regulate immune responses; therefore, they are a crucial target and tool for vaccination. The immunogenicity of antigens delivered by DCs has now been shown in patients with cancer. Basic principles of DC biology in the context of vaccination are discussed. By examining these principles, it is evident that certain parameters of vaccination with DCs need to be refined to improve efficacy. These include strategies for loading DCs with tumour antigens; manipulation of the different DC-maturation signals that can lead to different types of induced immune response; and promotion of the migration of DCs from the site of injection to draining lymph nodes. The importance of different DC subsets leading to the induction of distinct immune responses is reviewed. This complexity of the DC system requires that each DC subset be tested for efficacy at inducing antitumour responses in vivo . The ultimate ex vivo -generated DC vaccine will be heterogeneous and composed of several subsets, each of which will target a specific immune effector. The challenges of effective vaccination against chronic diseases, including cancer, are highlighted, particularly the exhaustion of antigen-specific T cells (owing to chronic activation) and the existence of other immune mechanisms that might hinder vaccine efficacy (for example, the development of tumour-antigen-specific regulatory T cells). Immune correlates of efficacy of DC vaccines are defined, including breadth of induced tumour-specific immunity, induction of tumour-specific effector and memory T cells, induction of T cells that kill tumour cells, and decreased numbers of T cells with regulatory function. Mouse studies have shown that the immune system can reject tumours, and the identification of tumour antigens that can be recognized by human T cells has facilitated the development of immunotherapy protocols. Vaccines against cancer aim to induce tumour-specific effector T cells that can reduce the tumour mass, as well as tumour-specific memory T cells that can control tumour relapse. Owing to their capacity to regulate T-cell immunity, dendritic cells are increasingly used as adjuvants for vaccination, and the immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer. A better understanding of how dendritic cells regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.

Differences in immune profiles of children and adults with COVID-19 have been previously described. However, no systematic studies have been reported from infants hospitalized with severe disease. We applied a multidimensional approach to decipher the immune responses of SARS-CoV-2 infected infants ( n  = 26; 10 subacute, 11 moderate and 5 severe disease; median age = 1.6 months) and matched controls ( n  = 14; median age = 2 months). Single cell (scRNA-seq) profiling of PBMCs revealed substantial alterations in cell composition in SARS-CoV-2 infected infants; with most cell-types switching to an interferon-stimulated gene (ISG hi ) state including: (i) CD14 + monocytes co-expressing ISGs and inflammasome-related molecules, (ii) ISG hi naive CD4 + T cells, (iii) ISG hi proliferating cytotoxic CD8 + T cells, and (iv) ISG hi naive and transitional B cells. We observe increased serum concentrations of both interferons and inflammatory cytokines in infected infants. Antibody responses to SARS-CoV-2 are also consistently detected in the absence of anti-IFN autoantibodies. Compared with infected adults, infants display a similar ISG signature in monocytes but a markedly enhanced ISG signature in T and B cells. These findings provide insights into the distinct immune responses to SARS-CoV-2 in the first year of life and underscore the importance of further defining the unique features of early life immunity. This work identified immune signatures of COVID-19 including broad Interferon signatures that are unique to infants. Compared with infected adults, infants display similar Interferon signatures in monocytes but enhanced signatures in T and B cells.

Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity. This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2. Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved.