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Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes.We hypothesized that CD4We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.Compared to post-HCT SCID patients with normal CD4Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.

Significance Immune response to infection is accompanied by active demethylation of thousands of CpG sites. Yet, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we investigated the role of DNA methylation in the regulation of innate immune responses to bacterial infections. We found that virtually all changes in gene expression in response to infection occur prior to detectable alterations in the methylome. We also found that the binding of most infection-induced transcription factors precedes loss of methylation. Collectively, our results show that changes in methylation are a downstream consequence of transcription factor binding, and not essential for the establishment of the core regulatory program engaged upon infection., DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis. We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.

Immunity to infectious disease involves a combination of host resistance, which eliminates the pathogen, and disease tolerance, which limits tissue damage. While the severity of most pulmonary viral infections, including influenza A virus (IAV), is linked to excessive inflammation, our mechanistic understanding of this observation remains largely unknown. Here we show that mitochondrial cyclophilin D (CypD) protects against IAV infection via disease tolerance. Mice deficient in CypD (CypD-/- mice) are significantly more susceptible to IAV infection despite comparable antiviral immunity. Instead, this susceptibility resulted from damage to the lung epithelial barrier caused by a significant reduction of IL-22 production by conventional NK cells in IAV-infected CypD-/- mice. Transcriptomic and functional data revealed that the compromised IL-22 production by NK cells resulted from dysregulated lymphopoiesis, stemming from increased cell death in NK cell progenitors, as well as the generation of immature NK cells that exhibited altered mitochondrial metabolism. Importantly, following IAV infection, administration of recombinant IL-22 abrogated pulmonary damage and enhanced survival of CypD-/- mice. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.

Humans vary in their susceptibility to infectious disease, partly due to variation in the immune response following infection. Here, we used single-cell RNA-sequencing to quantify genetic contributions to this variation in peripheral blood mononuclear cells, focusing specifically on the transcriptional response to influenza infection. We find that monocytes are the most responsive to influenza infection, but that all cell types mount a conserved interferon response, which is stronger in individuals with increased European ancestry. By comparing European American and African American individuals, we show that genetic ancestry effects on expression are common, influencing 29% of genes, but highly cell type-specific. Further, we demonstrate that much of this population-associated expression variation is explained by cis expression quantitative trait loci, which are enriched for signatures of recent positive selection. Our findings establish common cis-regulatory variants—including those that are differentiated by genetic ancestry—as important determinants of the antiviral immune response.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease, COVID-19, has demonstrated the devastating impact of a novel, infectious pathogen on a susceptible population. Here, we explain the basic concepts of herd immunity and discuss its implications in the context of COVID-19.

Humans display remarkable immune response variation when exposed to identical immune challenges. However, our understanding of the genetic, evolutionary, and environmental factors that impact this inter-individual and inter-population immune response heterogeneity is still in its early days. In this review, we discuss three fundamental questions concerning the recent evolution of the human immune system: the degree to which individuals from different populations vary in their innate immune responses, the genetic variants accounting for such differences, and the evolutionary mechanisms that led to the establishment of these variants in modern human populations. We also discuss how past selective events might have contributed to the uneven distribution of immune-related disorders across populations.

Summary Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans. To identify differences between antiviral mechanisms in humans and bats, we sequenced, assembled, and analyzed the genome of Rousettus aegyptiacus, a natural reservoir of Marburg virus and the only known reservoir for any filovirus. We found an expanded and diversified KLRC/KLRD family of natural killer cell receptors, MHC class I genes, and type I interferons, which dramatically differ from their functional counterparts in other mammals. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Based on our findings, we hypothesize that tolerance of viral infection, rather than enhanced potency of antiviral defenses, may be a key mechanism by which bats asymptomatically host viruses that are pathogenic in humans., Graphical Abstract, Highlights • High-contiguity genome assembly for Rousettus aegyptiacus, a host of Marburg virus • Expansion of NK cell receptors, MHC class I genes, and type I interferons • Genetic signatures of unique signaling in NK cell receptors in multiple bats • Enhanced infection tolerance may be an antiviral defense strategy in bats, The genome of the Egyptian fruit bat reveals how its immune defenses allow tolerance of pathogenic viruses.

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.