Research on human leukocyte antigen (HLA) molecules in coronavirus disease 2019 (COVID-19) raised high expectations but has yielded limited results. Augusto et al.'s recent study in Nature unveils a strong association of HLA-B*15:01 with asymptomatic COVID-19, representing an important contribution to genetics in COVID-19.

Humans express four different lipid antigen-presenting molecules, CD1a, CD1b, CD1c, and CD1d, that are differentially expressed on antigen-presenting cells and which recycle through different endosomal compartments. Huang et al. now answer the question on whether the four CD1 isoforms selectively bind certain lipids.

Regulatory T (Treg) cells play vital roles in immune homeostasis and response, including discrimination between self- and non-self-antigens, containment of immunopathology, and inflammation resolution. These diverse functions are orchestrated by cellular circuits involving Tregs and other cell types across space and time. Despite dramatic progress in our understanding of Treg biology, a quantitative framework capturing how Treg-containing circuits give rise to these diverse functions is lacking. Here, we propose that different facets of Treg function can be interpreted as distinct operating regimes of the same underlying circuit. We discuss how a systems immunology approach, involving quantitative experiments, computational modeling, and machine learning, can advance our understanding of Treg function, and help identify general operating and design principles underlying immune regulation.

Adjuvants are essential components of modern vaccines. One general mechanism underlying their immunostimulatory functions is the activation of pattern recognition receptors (PRRs) of innate immune cells. Carbohydrates - as essential signaling molecules on microbial surfaces - are potent PRR agonists and candidate materials for adjuvant design. Here, we summarize the latest trends in developing carbohydrate-containing adjuvants, with fresh opinions on how the physicochemical characteristics of the glycans (e.g., molecular size, assembly status, monosaccharide components, and functional group patterns) affect their adjuvant activities in aiding antigen transport, regulating antigen processing, and enhancing adaptive immune responses. From a translational perspective, we also discuss potential technologies for solving long-lasting challenges in carbohydrate adjuvant design.

The characterization of a new group of innate pattern recognition receptors detected in >500 species across the tree of life by Li et al. reveals surprising commonalities and peculiarities shared with other innate receptors. Receptor diversity within and among species opens the way to reconsidering the costs and benefits of innate immune recognition.

Recent studies have characterized ancient forms of cyclic GMP-AMP (cGAMP) synthase (cGAS)-like receptors (cGLRs) in bacterial and Drosophila immunity. Using bioinformatics and biochemical screening, Li et al. recently constructed and characterized >3000 cGLRs to reveal conserved mechanisms of nucleic acid sensing across animal immunity.

Klebsiella pneumoniae is among the most common antibiotic-resistant pathogens causing nosocomial infections. Additionally, it is a leading cause of neonatal sepsis and childhood mortality across the globe. Despite its clinical importance, we are only beginning to understand how the mammalian adaptive immune system responds to this pathogen. Further, many studies investigating potential K. pneumoniae vaccine candidates or alternative therapies have been launched in recent years. Here, we review the current state of knowledge on the adaptive immune response to K. pneumoniae infections and progress towards developing vaccines and other therapies to combat these infections.

'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19.

ADAR1 and ZBP1 are the only two mammalian proteins that contain Zα domains, which are thought to bind to nucleic acids in the Z-conformation. These two molecules are crucial in regulating diverse biological processes. While ADAR1-mediated RNA editing supports host survival and development, ZBP1-mediated immune responses provide host defense against infection and disease. Recent studies have expanded our understanding of the functions of ADAR1 and ZBP1 beyond their classical roles and established their fundamental regulation of innate immune responses, including NLRP3 inflammasome activation, inflammation, and cell death. Their roles in these processes have physiological impacts across development, infectious and inflammatory diseases, and cancer. In this review, we discuss the functions of ADAR1 and ZBP1 in regulating innate immune responses in development and disease.

Obesity is associated with the development of various complications, including diabetes, atherosclerosis, and an increased risk for infections, driven by dysfunctional innate immune responses. Recent insights have revealed that the availability of nutrients is a key determinant of innate immune cell function. Although the presence of obesity is associated with overnutrition of macronutrients, several micronutrient-deficiencies, including Vitamin D and zinc, are often present. Micronutrients have been attributed important immunomodulatory roles. In this review, we summarize current knowledge of the immunomodulatory effects of Vitamin D and zinc. We also suggest future lines of research to further improve our understanding of these micronutrients; this may serve as a stepping-stone to explore micronutrient supplementation to improve innate immune cell function during obesity.

The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E2 (PGE2) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE2 was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE2 plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack.

Vaccines have dramatically changed the COVID-19 pandemic. Over 30 vaccines that were developed on four main platforms are currently being used globally, but a deep dissection of the immunological mechanisms by which they operate is limited to only a few of them. Here, we review the evidence describing specific aspects of the modes of action of COVID-19 vaccines; these include innate immunity, trained innate immunity, and mucosal responses. We also discuss the use of COVID-19 vaccines in the African continent which is ridden with inequality in its access to vaccines and vaccine-related immunological research. We argue that strengthening immunology research in Africa should inform on fundamental aspects of vaccination, including the relevance of genetics, trained innate immunity, and microbiome diversity.

T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic pathways characterized by low nutrient requirements, effector T cells induce kinetically faster pathways to generate the biomass and energy needed for proliferation and cytokine production. Recent findings support the concept that alterations in metabolism also affect the epigenetics of T cells. In this review we discuss the connections between T cell metabolism and epigenetic changes such as histone post-translational modifications (PTMs) and DNA methylation, as well as the 'extra-metabolic' roles of metabolic enzymes and molecules. These findings collectively point to a new group of potential therapeutic targets for the treatment of T cell-dependent autoimmune diseases and cancers.

Tumors can evade conventional T cell recognition by rendering the HLA class I antigen presentation system defective. In a recent study, de Vries et al. reveal γδ T cells as key contributors to the efficacy of immune checkpoint blockade (ICB) against HLA-I-silenced cancers, highlighting a novel layer of surveillance against immune escape by tumors.

Resistance mechanisms have curbed the potential of immune checkpoint blockade (ICB) therapies. Understanding mechanisms that contribute to this resistance should reveal new targets for combinatorial therapy. Tank-binding kinase 1 (TBK1) represents such a target. In recent work by Sun et al., inhibition of TBK1 restored the efficacy of such treatments by sensitizing tumors to RIPK1 kinase-dependent inflammatory cell death.

Activation of Toll-like receptor 7 (TLR7) can induce lupus in mice, whereas activation of TLR9 can prevent it, even though both receptors interact with myeloid differentiation primary response gene 88 (MyD88) for downstream signaling. How TLR9 triggers anti-inflammatory responses in autoimmunity is unclear. Leibler et al. recently reported that TLR9 initiates anti-inflammatory signaling and inhibits lupus pathogenesis in a MyD88-independent but ligand-dependent manner.

Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.

The latent reservoir for HIV-1 prevents cure but is difficult to characterize due to the low frequency of latently infected cells and the absence of unique markers. Sun et al. used single cell analysis of T cell surface phenotypes to provide evidence for immune selection of reservoir cells.

Distinguishing between commensal and pathogenic bacteria to generate appropriate responses (tolerance vs. immunogenicity) is a key decision that the human immune system must make to maintain homeostasis. Recently, Clasen and colleagues reported a distinct allosteric interaction between bacterial flagellin and host Toll-like receptor 5 (TLR5), which may shed light on these differences.

Broadening immune responses through antigen spreading remains the 'Holy Grail' of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of chimeric antigen receptor (CAR)-T cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically heterogenous solid tumors through a mechanism crucially dependent on interferon (IFN)γ.