Immunity

Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells...

Inducible nucleosome remodeling at hundreds of latent enhancers and several promoters shapes the transcriptional response to Toll-like receptor 4 (TLR4) signaling in macrophages. We aimed to define the identities of the transcription factors that promote TLR-induced remodeling. An analysis strategy based on ATAC-seq and single-cell ATAC-seq that enriched for genomic regions most likely to undergo remodeling revealed that the transcription factor nuclear factor κB (NF-κB) bound to all high-confidence peaks marking remodeling during the primary response to the TLR4 ligand, lipid A...

In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation...

It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals...

Na+ /K+ -ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome...

Stress hormones can contribute to cancer progression, but how immune cells play a role in this process is unclear. In a recent study in Cancer Cell, He et al. showed that glucocorticoids potentiate metastasis by skewing neutrophils toward pro-tumorigenic functions.

Activation of the peripheral immune system contributes to stress-related neuropsychiatric symptoms. Recently in Nature, Cathomas et al. demonstrate that stress-induced social avoidance is mediated by monocyte-derived MMP8 that remodels the extracellular space of the nucleus accumbens.

Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.

IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense...

Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death...

Adjuvants play pivotal roles in vaccine development, enhancing immunization efficacy through prolonged retention and sustained release of antigen, lymph node targeting, and regulation of dendritic cell activation. Adjuvant-induced activation of innate immunity is achieved via diverse mechanisms: for example, adjuvants can serve as direct ligands for pathogen recognition receptors or as inducers of cell stress and death, leading to the release of immunostimulatory-damage-associated molecular patterns. Adjuvant systems increasingly stimulate multiple innate pathways to induce greater potency...

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules produced in cellular damage or stress, and they can activate the innate immune system. DAMPs contain multiple types of molecules, including nucleic acids, proteins, ions, glycans, and metabolites. Although these endogenous molecules do not trigger immune response under steady-state condition, they may undergo changes in distribution, physical or chemical property, or concentration upon cellular damage or stress, and then they become DAMPs that can be sensed by innate immune receptors to induce inflammatory response...

RIG-I-like receptors (RLRs) are crucial for pathogen detection and triggering immune responses and have immense physiological importance. In this review, we first summarize the interferon system and innate immunity, which constitute primary and secondary responses. Next, the molecular structure of RLRs and the mechanism of sensing non-self RNA are described. Usually, self RNA is refractory to the RLR; however, there are underlying host mechanisms that prevent immune reactions. Studies have revealed that the regulatory mechanisms of RLRs involve covalent molecular modifications, association with regulatory factors, and subcellular localization...

The cGAS-STING intracellular DNA-sensing pathway has emerged as a key element of innate antiviral immunity and a promising therapeutic target. The existence of an innate immune sensor that can be activated by any double-stranded DNA (dsDNA) of any origin raises fundamental questions about how cGAS is regulated and how it responds to "foreign" DNA while maintaining tolerance to ubiquitous self-DNA. In this review, we summarize recent evidence implicating important roles for cGAS in the detection of foreign and self-DNA...

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses...

Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis...

Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses...

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function...

While largely neglected over decades during which adaptive immunity captured most of the attention, innate immune mechanisms have now become central to our understanding of immunology. Innate immunity provides the first barrier to infection in vertebrates, and it is the sole mechanism of host defense in invertebrates and plants. Innate immunity also plays a critical role in maintaining homeostasis, shaping the microbiota, and in disease contexts such as cancer, neurodegeneration, metabolic syndromes, and aging...