How mammals mount an effective immune response against infectious agents remains unresolved. Here we identify microbial adhesion to myeloid cells as a critical initiating event that precedes pattern recognition receptor (PRR) engagement. Using a skin infection model with pathogenic bacteria and fungi, we demonstrate that neutrophil recruitment occurs in two sequential phases. The early phase is PRR-independent and instead driven by microbial adhesion, which engages the mechanosensitive ion channel Piezo1 to promote leukotriene (LT)B4 production. Together with interleukin-1α, LTB4 induces CXCL1 release, triggering neutrophil infiltration via the same circuit at play during sterile inflammation. By contrast, the late phase is toll-like receptor (TLR)- and CXCL2-dependent, marking a transition to the canonical, pathogen-driven response. Our findings uncover microbial adhesion as a previously unrecognized danger signal that activates innate immunity via mechanotransduction, revealing a paradigm of how immune responses to infection are initiated. Granucci and colleagues identify microbial adhesion to myeloid cells as a critical initiating event that precedes engagement of pattern recognition receptors.
Nod-like receptor family pyrin domain-containing 3 (NLRP3) is activated by many stimuli, and its dysfunction is involved in various inflammatory diseases. Activation of NLRP3 is thought to happen via a multistep process involving phase separation, conformational opening and oligomerization. However, how NLRP3 is released from its autorepressed conformation remains elusive. Here we report that activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1), previously known for its role in autophagy, bound NLRP3 to scaffold and allosterically activate NLRP3. AMBRA1 engaged the leucine-rich repeat and helical domain 2 subdomains of NLRP3 through its β-propeller domain and destabilized the closed, inactive conformation of NLRP3, facilitating adenosine triphosphate binding and transition of NLRP3 to the active state. AMBRA1 deficiency in monocytes or macrophages impaired NLRP3 activation and reduced inflammatory responses in mouse models of endotoxic shock, colitis and sepsis. Nanobodies blocking the interaction between AMBRA1 and NLRP3 inhibited NLRP3 activation, underscoring the therapeutic potential of targeting this interaction. Our study revealed the role of AMBRA1 in NLRP3 inflammasome assembly and activation, offering potential pharmacological targets for related diseases. Jiang and colleagues show that the adaptor protein AMBRA1 binds NLRP3 to destabilize the closed, inactive conformation of NLRP3 and facilitate binding of ATP and transition to the active state of NLRP3.
Natural killer (NK) cells leave distinct footprints on the HIV reservoir, leading to a smaller HIV reservoir size in individuals carrying the HLA-C2 allele. HIV escapes NK cell-mediated immunity through mutations in the viral proteins Vpu, Gag and Env.
Host immune responses that can target and eliminate HIV-1 reservoir cells during suppressive antiretroviral therapy are poorly understood. Here, analyzing over 6,000 proviral DNA amplicons from 104 individuals on long-term antiretroviral therapy, we found that carriers of HLA-C2 allotypes, which promote NK cell education via interactions with KIR2DL1, exhibited lower frequencies of intact proviruses. No protective effects of HLA-C2 alleles were observed during untreated infection, suggesting a selective vulnerability of reservoir cells to NK-cell-mediated immune activity under antiretroviral therapy. Supporting this, frequencies of KIR2DL1+ NK cells, particularly those coexpressing the activating HLA-E receptor NKG2C, were inversely correlated with frequencies of intact proviruses. Moreover, viral protein U variants that strongly downregulate HLA-C, increasing a missing-self response by KIR2DL1+ NK cells, were associated with smaller reservoirs in carriers of HLA-C2. Infected cells surviving long-term displayed elevated HLA-C expression, consistent with in vivo selection for resistance to KIR2DL1+ NK-cell-mediated immune clearance. Immune activity of KIR2DL1+ NK cells against viral reservoir cells was enhanced by NKG2C-HLA-E interactions, as sequence variants in HLA-E-restricted HIV-1 epitopes reduced NKG2C-dependent NK cell activation and were associated with higher frequencies of intact proviruses. These findings underscore the critical influence of host and viral genetic variation on reservoir persistence and highlight opportunities for leveraging innate immunity in HIV cure strategies.
The recent application of single-cell genomics to the investigation of immune-mediated arthritis has resulted in an explosion of information, including the discovery of lymphocyte, myeloid and fibroblast cell subsets proposed to be pathogenic. A challenge in the field is how to leverage these exciting but largely descriptive and correlative datasets to gain insights into causality and mechanisms of disease. In this Perspective, I describe emerging data and discuss ideas about how spatial transcriptomics, ex vivo mechanistic and organoid studies, and improved use of animal models based on human disease data can advance the understanding of immune-mediated arthritis pathogenesis, with a focus on rheumatoid arthritis. These insights can form the basis for designing new therapeutic strategies and implementing clinical trials. The concepts and approaches described here for arthritis may have broader applicability to other tissues and immune-mediated diseases.
A population of inflammatory monocytes differentiates into persistent lung-resident Gal-1+ myeloid cells that colocalize with and support the long-term maintenance and recall responses of influenza virus-induced tissue-resident memory CD8+ T cells.
After viral infections, tissue-resident memory T cells (TRM cells) are generated and reactivated rapidly upon re-exposure to previously encountered viral pathogens, providing immediate immune effector functions to limit infection at the site of viral entry. Here we found that a subset of newly recruited CCR2+ monocytes differentiated into memory-stage CCR2-tdTomato+ cells and persisted in the lung for more than 4 months after infection with the influenza virus. Selective depletion of the memory-stage CCR2-tdTomato+ cells reduced significantly the formation of lung CD8+ TRM cells and compromised secondary heterosubtypic immune protection. Memory-stage CCR2-tdTomato+ cells colocalized with lung CD8+ TRM cells and secreted galectin-1, which activated CD8+ T cells directly and enhanced transforming growth factor-β sensing. Intranasal administration of recombinant galectin-1 as an adjuvant for the influenza vaccine induced superior memory CD8+ T cell responses. Thus, the presence of a unique memory-like monocyte-derived subset provided crucial signals to establish and maintain functional CD8+ TRM cells in the lung.
A population of intramucosal GPR15-guided regulatory CD8+ T cells control intestinal inflammation by inducing cell death in inflammatory macrophages.
Type 2 inflammation is coordinated by remarkably durable CD4+ T helper 2 (TH2) cell responses, yet the cellular architecture that drives this chronic inflammation and prevents exhaustion remains poorly understood. To define the TH2 landscape in chronic type 2 inflammation, we established a mouse model of long-term pulmonary allergen exposure, finding that type 2 inflammation was broadly sustained over time and included an expanded T cell factor 1-expressing progenitor-like population. In vivo, lung TH2 progenitors were sufficient to both initiate and sustain type 2 inflammation, coupling self-renewal with effector cell differentiation. Transcriptomic and spatial deconstruction of chronic pulmonary TH2 responses identified interleukin-7 receptor signaling and lung tissue B cell infiltration in the context of tertiary lymphoid structure formation as key factors contributing to the maintenance of TH2 progenitors. Our data define the TH2 progenitor as a distinct cellular state arising during pathogenic chronic type 2 inflammation with a central role in sustaining TH2 responses over time.
Trauma disrupts the structure-function interplay of life, instantly engaging innate and adaptive immunity together with neuroendocrine, endovascular and metabolic axes. The immune response emerges from disturbances in overarching hallmarks of any living being-barrier systems, molecular communication and adaptation-further shaped by patient-specific, injury-specific and modern care-specific determinants. These factors drive adaptive or maladaptive immune trajectories, from restitution to chronic dysfunction or death. Multi-omics analyses of trauma cohorts now enable endotype discovery, providing a framework for mechanism-guided, spatiotemporal precision immunomodulation. This Review focuses exclusively on human studies to conceptualize major themes in clinical trauma immunology to guide future research.
High-throughput, high-dimensional profiling technologies have transformed the ability to generate and test hypotheses of human immunology. Investment in infrastructure has catalyzed the expansion of human cohorts and data repositories and enabled opportunities to predict disease risk, promote early diagnosis and design interventions that promote health.
The limited effectiveness of chimeric antigen receptor macrophage (CAR-M) therapy is largely due to poor tumor infiltration, reduced effector function and immune escape of target antigen-low tumors. Here we developed syncytial CAR-Ms (S-CAR-M) by fusing CAR-Ms with neutrophils. S-CAR-Ms accumulated in tumors more than conventional CAR-Ms because of chemokine-driven migration. By releasing neutrophil extracellular traps and reactive oxygen species inherited from neutrophils, S-CAR-Ms increased PtdSer exposure on tumor cells, leading to efficient phagocytosis of tumor debris through both the scFv-antigen and PtdSer-MerTK pathways. Thus, a single dose of S-CAR-Ms can reduce tumor burden, limit metastasis and prevent tumor recurrence in syngeneic and xenograft mouse models. Additionally, S-CAR-M therapy triggered antigen spreading, minimizing escape by target antigen-low tumor cells. S-CAR-Ms overcome limitations of conventional CAR-Ms toward solid tumors.
A comprehensive atlas of tissue-resident immune cells reveals where disease-risk variants regulate gene expression, helping connect genome-wide association study signals to disease mechanisms.
Notch2 deletion in dendritic cells (DCs), already known to impair type 2a DC development and intestinal immunity, is now demonstrated to promote dysbiosis and unleash inflammatory AXL-expressing type 3 DCs, driving preclinical autoimmunity.
Endothelial cells form the cell migration highways between organs. New results demonstrate that NOD2-dependent microbial sensing by these structural cells promotes antigen-specific T cell accumulation in gut-associated lymphoid tissues and protective mucosal immunity.
Microfold (M) cells transcytose luminal antigens to initiate mucosal adaptive immunity, but their role in organizing innate responses in Peyer's patches is unclear. Here we showed that Peyer's patch M cells organized an epithelial-group 3 innate lymphoid cell (ILC3) axis, establishing a spatial niche within the dome epithelium that drove ILC3 localization, proliferation and IL-22 production. We found that epithelial, but not hematopoietic, SPI-B was required for intestinal IgA responses to establish this niche. Single-cell profiling of intestinal SPI-B+ epithelial cells revealed that M cells were highly heterogeneous, displaying tissue- and pathogen-specific transcriptional programs. Using subset-specific genetic perturbation and whole-mount imaging, we found that this circuit relied on CCR6-dependent positioning cues and RANK-RANKL signaling to ILC3 to regulate Peyer's patch ILC3 homeostasis. Together, these findings identified Peyer's patch M cells as organizers that spatially coordinated innate cell localization, proliferation and cytokine production to maintain mucosal barrier defense.
Research on SARS-CoV-2 shows that effective immunity can arise from a balance between recalling existing immune memory and generating new variant-specific antibodies, with important implications for designing future vaccines.
For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024-2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets.
