Current Opinion in Immunology

Since the discovery of Toll and Toll-like receptors (TLRs) in the 90s, an extensive body of research has been performed to determine how Pattern Recognition Receptors (PRRs) recognise 'ligands' and signal. The families of PRRs now include membrane and cytosolic proteins, which broadly signal by forming large protein platforms or supramolecular organising centres (SMOCs). The concept of SMOC-driven signalling has led to the development of a set of assumptions, particularly for TLRs, based on experimental data, to explain the physiological consequences of PRR activation...

In tumors, immune cells organize into networks of different sizes and composition, including complex tertiary lymphoid structures and recently identified networks centered around the chemokines CXCL9/10/11 and CCL19. New commercially available highly multiplexed microscopy using cyclical RNA in situ hybridization and antibody-based approaches have the potential to establish the organization of the immune response in human tissue and serve as a foundation for future immunology research.

The microbiome regulates mammalian immune responses from early life to adulthood. Antigen presentation, orchestrating these responses, integrates commensal and pathogenic signals. However, the temporal and spatial specificity of microbiome impacts on antigen presentation and downstream tolerance versus inflammation remain incompletely understood. Herein, we review the influences of antigen presentation of microbiome-related epitopes on immunity; impacts of microbiome-based modulation of antigen presentation on innate and adaptive immune responses; and their ramifications on homeostasis and immune-related disease, ranging from auto-inflammation to tumorigenesis...

T follicular helper (Tfh) cells help direct the production of antibodies by B cells. In addition to promoting antibody responses to vaccination and infection, Tfh cells have been found to mediate antibody production to food antigens. Work over the past decade has delineated the specific phenotypes of Tfh cells that induce antibodies to food while also clarifying the divergent Tfh cell requirement for different food-specific antibody isotypes. Furthermore, Tfh and antibody responses to food can occur at multiple barrier sites - namely, skin, airway, and gut...

Signal integration is central to a causal understanding of appropriately scaled inflammatory responses. Here, we discuss recent progress in our understanding of the stimulus-response linkages downstream of pro-inflammatory inputs, with special attention to (1) the impact of cell state on the specificity of evoked gene expression and (2) the critical role of the spatial context of stimulus exposure. Advances in these directions are emerging from new tools for inferring cell-cell interactions and the activities of cytokines and transcription factors in complex microenvironments, enabling analysis of signal integration in tissue settings...

Despite its devastating human cost, the rapid spread and global establishment of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic had the benefit of providing unique insights into the intricate interplay between genetic, environmental, and socioeconomic factors, which collectively impact susceptibility to infection with SARS-CoV-2. Preceding the implementation of broad vaccination programs and assuming the absence of significant acquired immunity, examining the innate vulnerability to the virus becomes essential...

The innate immune system employs two different strategies to detect pathogens: first, it recognizes microbial components as ligands of pattern recognition receptors (pattern-triggered immunity [PTI]), and second, it detects the activities of pathogen-encoded effectors (effector-triggered immunity [ETI]). Recently, these pathogen-centric concepts were expanded to include sensing of self-derived signals during cellular distress or damage (damage-triggered immunity [DTI]). This extension relied on broadening the PTI model to include damage-associated molecular patterns (DAMPs)...

Interactions between the nervous system and the immune system play crucial roles in initiating and directing the type 2 immune response. Sensory neurons can initiate innate and adaptive type 2 immunity through their ability to detect allergens and promote dendritic cell and mast cell responses. Neurons also indirectly promote type 2 inflammation through suppression of type 1 immune responses. Type 2 cytokines promote neuronal function by directly activating or sensitizing neurons. This positive neuroimmune feedback loop may not only enhance allergic inflammation but also promote the system-wide responses of aversion, anaphylaxis, and allergen polysensitization that are characteristic of allergic immunity...

Microbiota-derived antigens play a critical role in the development of both the mucosal and systemic B cell repertoires; however, how glycan epitopes promote B cell repertoire selection is only recently being understood. The production of glycan-derived antigens by individual microbes within a host can be dynamic and influenced by interactions within other members of microbial communities, the composition of diet, and host-derived contents, including those of the mucosal immune system. The size and complexity of the emerging neonatal B cell repertoire are paralleled by the acquisition of a diverse microbiota from maternal and environmental sources, which is now appreciated to exert long-lasting influences on the nascent B cell repertoire...

Immune and tissue homeostasis is achieved through balancing signals that regulate cell survival, proliferation, and cell death. Recent studies indicate that certain cell death programs can stimulate inflammation and are often referred as 'immunogenic cell death' (ICD). ICD is a double-edged sword that can confer protection against pathogen infection but also cause tissue damage. Necroptosis is a key ICD module that has been shown to participate in host defense against pathogen infection, tissue homeostasis, and cancer response to immunotherapy...

TCF-1+ CD8+ T cell populations have emerged as critical determinants for long-lived immunological memory. This cell population has stem-like properties and is implicated in improved disease outcomes by driving sustained killing of infected cells and maintaining the immune-cancer equilibrium. During an immune response, several factors, including antigen deposition and affinity, the inflammatory milieu, and T cell priming dynamics, aggregate to skew CD8+ T cell differentiation. Although these mechanisms are altered between acute and chronic disease settings, phenotypically similar stem-like TCF-1+ CD8+ T cell states are formed in each of these settings...

All organisms must defend themselves against viral predators. This includes bacteria, which harbor immunity factors such as restriction-modification systems and CRISPR-Cas systems. More recently, a plethora of additional defense systems have been identified, revealing a richer, more sophisticated immune system than previously appreciated. Some of these newly identified defense systems have distant homologs in mammals, suggesting an ancient evolutionary origin of some facets of mammalian immunity. An even broader conservation exists at the level of how these immunity systems operate...

The unconventional type I interferons IFNε and IFNω and type III interferon IFNλ are gradually emerging as tissue-specific cytokines in defence of mucosal tissues. This review provides an overview of the distinct features and functions that define these IFNs as protective factors in the respiratory, gastrointestinal and reproductive tracts, highlighting their immunoregulatory roles against pathogens while maintaining tolerance against commensal microbes. In particular, we discuss recent advances in our understanding of the constitutively expressed IFNε and its role in protecting against mucosal infections, inflammation and cancers...

The delicate balance between protective immunity against pathogens and the prevention of autoimmunity requires finely tuned generation and function of regulatory CD4+ T (Treg) cells. Here, we review recent progress in the understanding of a complex set of cues, which converge on Treg cells in lymphoid and nonlymphoid organs and in tumors and how these cues modulate Treg functions. We highlight the versatility of Treg cells underlying their ability to dynamically adapt to local microenvironments and perform a wide range of functions that extend beyond the archetypal role of Treg cells in moderating adverse effects of immune response-associated inflammation and in suppressing autoimmunity...

Immune cells in the tumor microenvironment play a crucial role in cancer prognosis and response to immunotherapy. Recent studies highlight the significance of tumor-infiltrating B cells and tertiary lymphoid structures as markers of favorable prognosis and patient-positive response to immune checkpoint blockers in some types of cancer. Although the presence of germinal center B cells and plasma cells in the tumor microenvironment has been established, determining their tumor reactivity remains challenging. The few known tumor targets range from viral proteins to self and altered self-proteins...

Single-cell RNA sequencing (scRNAseq) and Variable, Diversity, Joining (VDJ) profiling have improved our understanding of B-cells. Recent scRNAseq-based approaches have led to the discovery of intermediate B-cell states, including preplasma cells and pregerminal centre B-cells, as well as unveiling protective roles for B-cells within tertiary lymphoid structures in respiratory infections and cancers. These studies have improved our understanding of transcriptional and epigenetic control of B-cell development and of atypical and memory B-cell differentiation...

Plasma cells correspond to the last stage of B cell differentiation and are professional antibody-secreting cells. While most persist for only few days, some may survive for weeks to years in dedicated survival niches. The determination of plasma cell survival rate seems to rely both on intrinsic and extrinsic factors. Although often opposed, the deterministic and environmental models for plasma cell longevity are certainly overlapping. Understanding the contribution and the regulation of these different factors is paramount to develop better vaccines but also to target malignant plasma cells...

Gasdermins are membrane pore-forming proteins that cause pyroptosis, an inflammatory cell death in which cells burst and release cytokines, chemokines, and other host alarm signals, such as ATP and HMGB1, which recruit and activate immune cells at sites of infection and danger. There are five gasdermins in humans - gasdermins A to E. Pyroptosis was first described in myeloid cells and mucosal epithelia, which express gasdermin D and activate it when cytosolic sensors of invasive infection or tissue damage assemble into large macromolecular structures, called inflammasomes...

In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferon-stimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, including BST2, CD74, CH25H, DAXX, IFI6, IFITM1-3, LY6E, NCOA7, PLSCR1, OAS1, RTP4, and ZC3HAV1/ZAP, in restricting SARS-CoV-2 infection and discuss the virus's countermeasures. By synthesizing the latest research on SARS-CoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics...

The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways...