Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

Background: COVID-19 is currently a global pandemic, but the response of human immune system to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unclear. Noncoding RNAs serve as immune regulators and thus may play a critical role in disease progression. Methods: We performed multi-transcriptome sequencing of both noncoding RNAs and mRNAs isolated from the red blood cell depleted whole blood of moderate and severe COVID-19 patients. The functions of noncoding RNAs were validated by analyses of the expression of downstream mRNAs. We further utilized the single-cell RNA-seq data of COVID-19 patients from Wilk et al. and Chua et al. to characterize noncoding RNA functions in different cell types. Results: We defined four types of microRNAs with different expression tendencies that could serve as biomarkers for COVID-19 progress. We also identified miR-146a-5p, miR-21-5p, miR-142-3p, and miR-15b-5p as potential contributors to the disease pathogenesis, possibly serving as biomarkers of severe COVID-19 and as candidate therapeutic targets. In addition, the transcriptome profiles consistently suggested hyperactivation of the immune response, loss of T-cell function, and immune dysregulation in severe patients.

Exosomes have emerged as a novel approach for the treatment and diagnosis of cancer after RNA content was discovered in exosomes in 2007. As important meditators of intercellular communication, exosomes have become a strong focus of investigation for researchers in the past decade, as witnessed through the exponential increase of research on exosomes. The capability of exosomes to transfer functionally active cargo highlights their importance as promising biomarkers and diagnostic molecules, as well as prospective drug delivery systems. The accessibility of exosomes in nearly all biofluids additionally alludes to its unprecedented ability in various types of cancers due to its extensive impact on tumor formation and progression. This review analyzes the role of exosomal long RNA species, which is comprised of mRNA, lncRNA, and circRNA, in tumor formation and progression, with an emphasis on their potential as future diagnostic biomarkers and treatment vectors in cancer biology. Their alignment with the development of exosomal databases is further examined in this review, in view of the accumulation of studies published on exosomes in the past decade.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0823-z) contains supplementary material, which is available to authorized users.

Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell–cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.

CD4+CD8+ double-positive (DP) thymocytes, which are extremely sensitive to apoptosis, specifically up-regulate Bcl-xL to extend their lifespan. Deletion of the Bcl-xL gene leads to premature apoptosis of the thymocytes. In this study, we show that stabilization of β-catenin, a critical coactivator for T cell factor (TCF), enhances DP thymocyte survival via up-regulating Bcl-xL. Spontaneous or glucocorticoid-induced thymocyte apoptosis was associated with reduced levels of β-catenin and Bcl-xL. Transgenic expression of a stabilized β-catenin protected DP thymocytes from both spontaneous and glucocorticoid-induced apoptosis, resulting in significantly increased thymic cellularity. Compared with the wild-type mice, both protein and transcript levels of Bcl-xL were significantly increased in thymocytes of β-catenin transgenic mice. In addition, TCF-1 as well as β-catenin were able to stimulate transcriptional activity of the reporter driven by a Bcl-xL promoter. β-Catenin/TCF is thus able to act as a signal to up-regulate Bcl-xL levels in DP thymocytes, resulting in their enhanced survival.

Productive engagement of TCR results in delivering signals required for T cell proliferation as well as T cell survival. Blocking TCR-mediated survival signals, T cells undergo apoptosis instead of proliferation upon TCR stimulation. During the activation process, T cells produce IL-2, which acts as an extrinsic survival factor. In addition, TCR stimulation results in up-regulation of Bcl-xL to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-θ is required for enhancing the survival of activated CD4+ T cells by up-regulating Bcl-xL. In response to TCR stimulation, CD4+ PKC-θ−/− T cells failed to up-regulate Bcl-xL, and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC-θ-deficient primary CD4+ T cells, small interfering RNA-mediated knockdown of PKC-θ in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-xL was sufficient to inhibit apoptosis observed in PKC-θ knockdown cells. Furthermore, ectopic expression of PKC-θ stimulated a reporter gene driven by a mouse Bcl-xL promoter. Whereas an inactive form of PKC-θ or knockdown of endogenous PKC-θ led to inhibition of Bcl-xL reporter. PKC-θ-mediated activation of Bcl-xL reporter was inhibited by dominant-negative IκB kinase β or dominant-negative AP-1. Thus, the PKC-θ-mediated signals may function not only in the initial activation of naive CD4+ T cells, but also in their survival during T cell activation by regulating Bcl-xL levels through NF-κB and AP-1 pathways.

Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.

RORγt regulates TH17 differentiation, thymic T cell development and lymph node genesis. Although elimination of RORγt prevents TH17-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified two amino acid mutations in RORγt (RORγtM) that preferentially disrupted TH17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH17 differentiation, but maintained normal thymocyte development and lymph node genesis, except for Peyer’s patches. RORγtM showed reduced ubiquitination at K69 that is selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17-mediated autoimmunity, but do not affect thymocyte development and induce lymphoma.