Antigenic and environmental stimuli sensed by innate and adaptive immune cells trigger cognate functions that allow the coordination of the appropriate immune response. In this issue of Immunity, Tzerpos et al. and Jay et al. demonstrate that chromatin…
Accumulating evidence implicates sensory neurons in tumor progression, but signals linking nociceptive activity to impaired antitumor immunity remain unclear. In a recent issue of Cell, Ho et al. show that nociceptor activation impedes TLS assembly thr…
Candida albicans induces Th17 cells, but their origins remain unresolved. In this issue of Immunity, Martini et al. show that the mouth is a reservoir for fungal Th17 cells that adopt pathogenic signatures in the gut during Crohn’s disease.
The unprecedented recent advancement in the field of interoception (sensing self) has introduced neuromodulation as a realistic treatment approach. Shibuya et al. identified an ear-to-lung reflex in which activation of auricular-innervating TRPV1+ vaga…
Sepsis lacks effective therapeutic interventions. Fish et al. examine sepsis patients and identify three temporal immune states with distinct resistance, disease tolerance, and resilience program trajectories. Early and late immune responses do not ali…
Cytokine cues reshape how chromatin folds to control immune gene activity. Jay et al. show that cytokine signals reposition the Ets1 super-enhancer toward the geometric center of the locus and sustain Ets1 expression required for helper T cell differen…
The role of noncoding lncRNAs in human disease is difficult to ascertain. Yang-Fischer et al. identify lnc15 (2310015A10Rik/ENSMUSG00000097729) as a cytoplasmic brake on intestinal inflammation. lnc15 expression is decreased in active human inflammator…
Ginhoux and colleagues review the mechanisms underlying the impact of obesity on cancer susceptibility, progression, and response to therapy. They discuss how metabolic stress reprograms myeloid cells, particularly macrophages, driving chronic inflamma…
The intestinal barrier harbors numerous intraepithelial lymphocytes (IELs) that promote tissue integrity and whose dysfunction contributes to disease. Earley et al. studied the G-protein coupled receptor signals regulating IEL movement and function and…
Recent studies have expanded the field of autophagy in immunity to include related but incompletely understood noncanonical autophagy processes. Deretic reviews these advancements in the context of immunity, offering a unifying framework for canonical …
UVR-damaged melanocytes evade immune attack despite harboring many mutations. Lo et al. show that MITF, a transcriptional regulator crucial to melanocyte identity, directly induces the immune checkpoint molecule PD-L1. This intrinsic tolerance program …
Generating mice that express human antibodies is a lengthy and labor-intensive process. Knocking in human gene segments into mice has potential, but how large a gene segment can be knocked into a zygote? Nair et al. insert a 155-kb human VH locus direc…
Some regulatory T (Treg) cells differentiate at peripheral sites in response to antigens derived from innocuous sources. In this issue of Immunity, Chi et al. examine an extensive array of T cell receptors with specificity for self, microbial, or dieta…
Genetic associations point to a connection between lysosomal function and neurodegeneration. In this issue of Immunity, Balak et al. and Tejwani et al. show that genetically distinct lysosomal insults converge on a shared MITF/TFE-driven epigenetic pro…
The metabolic mechanisms linking chronic TCR stimulation to T cell exhaustion remain incompletely understood. Mitra and colleagues show that sustained MEK signaling drives the bioenergetic demands of chronic activation to promote terminal exhaustion, w…
High endothelial venules require specialized morphology and PNAd expression to support lymphocyte homing; however, the transcriptional mechanisms coordinating these defining features have remained unclear. Bi et al. identify XBP1-dependent and CREB3L2-…
Dendritic cells (DCs) can acquire distinct functional states. To examine how different DC states orchestrate anti-tumor immunity, Koufaki et al. develop mouse models to label and ablate CCR7+ DCs and find that this activation state is essential for tum…
Mutations in proteins with roles in lysosomal function, including progranulin, are linked with neurodegenerative diseases. Tejwani, Heffner, et al. demonstrate that lysosomal dysfunction is sufficient to drive epigenetic, transcriptional, and functiona…
Lysosomal dysfunction is associated with neurodegeneration. Balak et al. examine the cell-specific effects of lysosomal dysfunction in an MPS-IIIA (Sgsh−/−) model and find that microglia are disproportionately affected. Mechanistically, the MITF/TFE tr…
Negative regulatory ligands have been underexplored for B cells. Su et al. identify fibrinogen-like protein 1 (FGL1) as a new inhibitory ligand for a transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) on a subset of …
Fang and Schneider review how bile acids connect host metabolism, microbial ecology, and tumor immunity. They present a spatial and cell-type-aware framework for bile acid immunomodulation and discuss therapeutic opportunities to remodel bile acid-immu…
Adherent cells mimic the mechanical properties of their surroundings, becoming stiffer in more rigid environments and softer in more compliant ones. Elbanna et al. find that this environmentally induced stiffening response shapes metastatic site distri…
Using CRISPR-based TCR editing, Chi et al. systematically compare gut TCRs recognizing dietary, microbial, and self-antigens to define the principles that govern peripheral Treg cell differentiation. They find that TCR identity encodes pTreg cell gener…
How brain-resident microglia regulate T cell immunity during glioma progression remains unclear. Qian et al. show that disease-associated microglia (DAMs) are not fixed suppressors but instead evolve with tumor stage. DAMs transition from antigen-prese…
High endothelial venules (HEVs) facilitate lymphocyte entry into lymph nodes by displaying peripheral node addressin (PNAd), yet how PNAd is regulated remains poorly understood. Jacobs et al. reveal that autophagy preserves HEV identity and function by…
Macrophage plasticity and function involve precise regulation of transcriptional programs. Tzerpos et al. find that the transcription factor BACH1 establishes early chromatin accessibility while maintaining transcriptionally repressive states in naive …
Innate immune recognition of bacteria is thought to center on cell-surface or endosomal pattern recognition receptors such as TLRs. Ragland et al. identify an intraphagosomal cyclic dinucleotide (CDN)-host transporter-STING axis, wherein cytoplasmic ST…
Bioelectronic technologies are being deployed to treat many inflammatory conditions using transcutaneous auricular nerve stimulation. Shibuya et al. employ viral tracing, chemogenetics, and optogenetics to unveil a sensory skin-lung vagal reflex that s…
Martini, Hofmann, et al. identify C. albicans-specific Th17 cells targeting fungal EV proteins that predominantly reside in the human oral mucosa at homeostasis. However, these oral-residing cells exhibit TCR overlap with gut Th17 cells. During intesti…
by Iker Ramírez Lapeña, Stephanie C. Ganal-Vonarburg
While pregnancy suppresses systemic immunity to tolerate the fetus, adaptations of the gut remain unclear. In a recent issue of Nature, Huang et al. show that reproduction increases intestinal eosinophils, shifting intestinal stem cell fate toward gobl…
Metabolic alterations and neutrophils define the pre-metastatic niche, but the mechanisms connecting them remain incompletely understood. In this issue of Immunity, Qian et al. show that endothelial-derived palmitate induces neutrophils to release lipo…
Extracellular ATP (eATP) is an immunogenic danger signal. In this issue of Immunity, Hu et al. report that in the tumor microenvironment, eATP signals through the receptor P2RY2 on cancer cells, triggering the COX-PGE2 pathway and thereby immune suppre…
Similar to CD8+ T cells, stem-like CD4+ T cells sustain responses to tumors, chronic infections, and inflammation. In this issue of Immunity, Wen et al. and Agesta et al. reveal EOMES as a critical regulator of stem-like CD4+ T cell maintenance and dif…
Aging and chronic inflammation alter hematopoiesis, impacting the hematopoietic progenitor populations in the bone marrow. In this issue of Immunity, Yao et al. show that the canonical type 2 cytokine interleukin 4 reverses age-related hematopoietic an…
In April of this year, our community lost one of its most brilliant and beloved members, Philippe Bousso. With his unique scientific vision, love of technical innovation, and his generous and kind spirit, Philippe touched many of our lives and gave us …
Precise control of cytosolic nucleic acid sensing is essential for immune homeostasis, yet endogenous metabolites that regulate both DNA and RNA sensing remain unidentified. Wang et al. identify FAD as a natural brake restraining both DNA- and RNA-trig…
Mitra et al. examine how chronic antigen stimulation of CD8+ T cells leads to this metabolic dysfunction and find that MEK-driven ATP demand drives terminal T cell exhaustion by supporting protein synthesis at the expense of NAD+-dependent proliferatio…
Current CRISPR-Cas9 methods are restricted to small genomic edits. Nair et al. report the rapid generation of knock-in mice expressing human immunoglobulin (Ig) by precise deletion of the 2.4-Mb murine Ig heavy-chain locus and insertion of a 155-kb hum…
The ability to maintain tolerance at mucosal barrier surfaces is critical for immune homeostasis. Yang et al. identify Bhlhe40 as a central regulator linking innate and adaptive intestinal immunity. By coordinating ILC3 effector responses with RORγt⁺ a…
Recurrence is a major clinical challenge in hepatocellular carcinoma (HCC). Gu et al. examine human HCC samples to identify drivers of disease recurrence and find that inhibiting the cholesterol esterification enzyme SOAT1 impairs tumor redox resilienc…
West Nile virus and other neurotrophic arboviruses can cause life-threatening encephalitis. Lewy et al. identify a cross-organ immune circuit where viral pattern sensing in the skin potently counteracts viral encephalitis. Mechanistically, the establis…
Extrinsic factors that support CD8+ T cell responses during chronic viral infection are incompletely defined. Gago da Graça et al. identify a crucial role for B cells in triggering type I interferon production, thereby promoting T cell effector formati…
Extracellular ATP (eATP) is associated with immune suppression in the tumor microenvironment (TME) via its metabolite adenosine. Hu et al. find that immunotherapy increases eATP within the TME and drives immune suppression through direct binding of the…
Aerobic glycolysis, a hallmark of cancer, preferentially converts pyruvate into lactate. Guo et al. demonstrate that tumor aerobic glycolysis drives lactate production through PKM2-mediated phosphorylation and activation of LDHA. Lactate directly binds…
Understanding FcγR engagement and signaling is central to improving monoclonal antibody therapeutics. Using structural, biophysical, and cellular immunology approaches, Fisher et al. demonstrate how disparate off rates drive the agonism and antagonism …
The transcription factor Eomes orchestrates the differentiation and maintenance of an exhausted-like Th cell lineage that is transcriptionally and functionally distinct from conventional effector and memory Th subsets. This lineage is amplified by 4-1B…
CD4+ T helper cells are essential for adaptive immunity; however, factors governing their maintenance and function during chronic antigen exposure remain unclear. Wen et al. identify a precursor T cell population, dependent on TOX, EOMES, and MYB, that…
Lymph nodes initiate protective T cell responses to Mycobacterium tuberculosis yet also serve as sites of chronic infection. Shamskhou et al. shed light on this paradox by showing a shift from early dendritic cell-driven Th1 cell priming to monocyte-de…
No specific prophylaxis or treatment exists for West Nile virus (WNV) or related orthoflavivirus infections. Cervantes Rincón et al. characterize human antibody responses to WNV and identify protective epitopes on the virus envelope protein. A potent m…
Neutrophils have the capacity to both support and block tumor growth depending on their polarization state. Here, Pei et al. find that IFN-γ produced during immunotherapy induces PD-L1 expression by neutrophils with an aged phenotype that drives therap…
The mechanisms by which anti-RIPR antibodies inhibit parasite invasion are poorly understood. Williams et al. analyze monoclonal antibodies against the Plasmodium falciparum blood-stage protein RIPR and reveal that combinations of non-neutralizing anti…
How IL-23 drives an inflammatory Th17 cell state is poorly understood. Yang et al. identify two coordinated mechanisms specific to IL-23R signaling: the recruitment of CHD1 to stabilize RORγt expression and function and the blockade of glucocorticoid r…
Th17 cells can either preserve homeostasis or drive inflammation in tissues; however, the mechanisms that maintain homeostatic phenotypes are not well defined. Yang et al. uncover a cell-intrinsic glucocorticoid circuit and the underlying gene network …
Borden et al. examine primary, treatment-naive squamous cell carcinoma (SCC) tumors to determine the impact of immunoediting. Comparison of SCC tumors from immunocompetent and immunosuppressed patients demonstrates immune-mediated sculpting of the tumo…
Altered astrocyte-microglia interactions have been implicated in the pathogenesis of Alzheimer’s disease, but the underpinning mechanisms remain unclear. Zhang and colleagues show that astrocytic PAD2-mediated citrullination of vimentin activates micro…
The presence of tertiary lymphoid structures (TLSs) associates with improved anti-tumor immunity, and as such, understanding why some tumors develop TLSs is of prime interest. In the current issue of Cancer Cell, Kirschstein et al. demonstrate that TGF…
by Mingyang Yin, Tao Liang, Yumeng Zhang, Guangchuan Wang, Wei Yang, Chenqi Xu
Cholesterol metabolism is an essential component of all immune cells. Xu and colleagues review the immunological functions of cholesterol metabolites and proteins and discuss how distinct cholesterol metabolic programs fulfil the metabolic and signalin…
Fibroblasts are highly attuned for immune crosstalk within lymphoid tissues. In this issue of Immunity, Alouche et al. provide insight into how fibroblast immunoregulatory phenotypes are acquired and maintained, revealing that Ccl19hi fibroblastic reti…
Systemic lupus erythematosus is characterized by autoantibodies against nuclear antigens. In this issue of Immunity, Al Souz et al. report that kidney damage in lupus nephritis is sustained by stem-like CD8+ T cells that migrate from lymphoid tissues a…
Preservation of host fitness is a common feature of longevity and immunity to infection. In this issue of Immunity, Triana-Martinez et al. reveal that p16High senescence-associated immune cells promote disease tolerance and healthy aging. Mechanistical…
Research that is done but never shared does not make a sound. Science communication can take many forms and has many audiences, from research colleagues to the general public. Here, investigators discuss the importance of engaging in the dissemination …
Chronic inflammation and aging skew hematopoiesis toward myelopoiesis. Starting with a screen to identify signals capable of restoring lymphoid lineage commitment in HSPCs, Yao et al. find that exogenous interleukin 4 can drive lymphoid differentiation…
Patients with psoriasis show a durable clinical response to the anti-IL-23 biologic, risankizumab, even after treatment cessation. Here, Jiang et al. generate a longitudinal single-cell and spatial transcriptomics atlas of patients pre- and post-treatm…
Lobel, Fonseca-Pereira, et al. demonstrate that dietary sulfur amino acids (Saa) enhance anti-tumor immunity in colon cancer. A high-Saa diet expands the bacterium Mucispirillum schaedleri, which activates a natural killer T cell-dendritic cell axis to…
B cell infiltration in high-grade serous ovarian cancer associates with favorable prognosis. Nathan et al. show that tumor-draining lymph nodes in patients lack active germinal center responses and instead harbor quiescent tumor-reactive memory B cells…
Exercise is increasingly linked to improved immune function across diseases, yet the underlying mechanisms remain incompletely understood. Meisel et al. synthesize how acute exercise and sustained training reshape immune-cell trafficking and function t…
T follicular helper 13 (Tfh13) cells are required for anaphylactic IgE responses, yet how these cells arise is unclear. Lee et al. show that allergen sensitization drives CCR8-dependent trafficking of ILC2s to lymph nodes, where they provide early IL-4…
Diet impacts gut microbes and, subsequently, host immunity, but our understanding of the mechanisms driving this axis remains incomplete. Hattori-Muroi, Maruta, Takahashi, et al. show that dietary soy promotes colonization of commensals that cooperativ…
The role of non-infiltrating aged CD8+ T cells in brain function remains unclear. Sucharov et al. reveal that aged circulating cytotoxic T cells are drivers of age-related cognitive decline. Removal of aged T cells, or their secreted factor granzyme K,…
T follicular helper (Tfh) cells are essential for humoral immunity but can promote autoimmunity when dysregulated. Wang et al. identify a mevalonate pathway-dependent program in which GGPP supports Tfh cell differentiation by sustaining surface protein…
Under homeostatic conditions, murine dendritic cells (DCs) undergo a tolerogenic activation termed homeostatic maturation, preventing autoimmunity by inducing tolerance to innocuous antigens; whether this process occurs in humans is unknown. In this is…
by Dominic S. Albao, Shashank D. Nagaraja, Matthew E. Pipkin
CD8+ T cells responding to chronic infections are functionally and spatially heterogeneous. In this issue of Immunity, Shen et al. and Geng et al. demonstrate that the transcription factors KLF2 and KLF3 have integrated but opposing roles in regulating…
Severe pediatric autoimmune diseases (AD) have limited therapeutic options. In a recent issue of Nature Medicine, Becilli et al. report a case series where CD19 CAR T cell treatment of pediatric AD patients induced rapid and durable remissions with man…
The gut microbiome contributes to age-related cognitive decline, but signaling mechanisms remain unclear. In a recent issue of Nature, Cox et al. show that P. goldsteinii-derived fatty acids activate myeloid cells, thus inducing inflammation that disru…
Defining correlates of HIV rebound upon antiretroviral therapy (ART) interruption can advance HIV cure research. In this issue of Immunity, Ma et al. analyze immunophenotypes and transcriptomes from multiple clinical trials, linking T and NK cell subse…
Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving…
The mechanisms linking defective protein prenylation to systemic inflammation in mevalonate kinase deficiency remain unclear. Munoz et al. reveal that mice and humans with MKD have defective NK cells, with impaired granule trafficking, reduced cytotoxi…
CD8+ T cells must retain functional resilience as they traverse diverse environments. Scaglione et al. reveal how the integrated stress response enables CD8+ T cells to engage alternate biosynthetic modes under environmental stress that prevent dysfunc…
Ulezko Antonova et al. examine plasmacytoid dendritic cells (pDCs) in lymphoid tissues from infancy to adulthood and identify a cycling population of pDCs in fetal and infant lymphoid organs that is found only in the bone marrow in adults. pDCs in sepa…
Geng et al. identify KLF2 as a central regulator of CX3CR1+ effector-like exhausted CD8+ T cells during chronic infection. KLF2 is uniquely expressed and both necessary and sufficient for this state. Disrupting the KLF2-dependent program enhances viral…
Tumor-associated macrophages (TAMs) can limit anti-tumor immunity. Sun et al. find that SPP1+ TAMs are enriched in tumors across cancer types and associated with resistance to immune checkpoint blockade. Mechanistically, SPP1 interacts with TRIM21 to l…
Advancements in human genetics have catalyzed rapid discovery in immunology. Graham and Xavier review how functional genomics and chemical biology have joined forces to uncover mechanisms of mucosal immunity and the pathophysiology of inflammatory bowe…
Therapeutic monoclonal antibodies are central to cancer treatment but often show incomplete efficacy. Cheng et al. demonstrate that transient host-cell glycoengineering to reduce N-glycan trimming strengthens IgG-FcγRIIIa bond resilience under vascular…
Pre-metastatic niche formation is a pivotal driver of breast cancer lung metastasis; however, the mechanisms underlying changes in vascular endothelial permeability remain unclear. Qian et al. demonstrate that triple-negative breast cancer-induced palm…
TREX1, but not other DEDDh exonucleases, restrains cGAS-STING activation by cytosolic DNA. Zhu et al. examine the basis for this specificity and define a modular double-stranded DNA (dsDNA)-recognition architecture within TREX1 comprising R128, a subst…
Specialized fibroblastic reticular cell (FRC) subsets in lymph nodes orchestrate the compartmentalization that guides immune cell migration, interaction, and function. Alouche et al. examine the signals governing FRC differentiation and identify a Notc…
MAIT cells acquire effector-memory and tissue-residency programs in the thymus. Paiva et al. demonstrate that MAIT cells can be selected by epithelial cells and egress the thymus at several developmental stages with subset-specific tissue tropisms and …
Loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus. Al Souz et al. find that kidney-infiltrating CD8+ T cells differentiate from stem-like precursors in renal lymph nodes and c…
Intestinal microbiota can have both local and systemic effects on immunity and inflammation. Here, Yu et al. find that intestinal dysbiosis exacerbates atopic dermatitis pathology. Shifts in microbial abundances lead to elevated systemic levels of micr…
Using scRNA-seq of skin-innervating neurons, Voisin et al. show that skin-projecting nociceptor subpopulations differentially integrate the inflammatory response during allergic contact dermatitis. Although peptidergic TRPV1+ neurons control neutrophil…
Memory T (TMEM) cells are designated as either circulating (Tcircm) or tissue-resident (Trm) populations. In this review, Jameson and Hamilton examine the attributes of Tcircm cells and discuss the features and functional heterogeneity of distinct Tcir…
Tissue-resident memory T (TRM) cells provide local, organ-specific immunity and are shaped by their position within these tissues. This review outlines how priming-associated programming, niche-level microenvironments, and local antigen exposure define…
Although B cell development is a well-studied field, we are only beginning to appreciate the diversity and complexity of plasma cell formation and function. In this review, Fields and Bhattacharya discuss factors impacting plasma cell heterogeneity and…
Long-lived plasma cells maintain antibody titers that sustain humoral immunity, yet the physiological cues regulating their persistence remain incompletely understood. In this issue of Immunity, Zhu et al. reveal that fasting-induced β-hydroxybutyrate …
Regulated cell death is critical for both homeostasis and the response to infection. In this perspective, Tait and Oberst discuss how sub-lethal activation of canonical cell death pathways has lasting impacts on cells and tissues. These near-death cell…
Designing a universal influenza vaccine must address not only viral antigenic drift but also genetic variability in human antibody responses. In this issue of Immunity, two studies from the Karlsson-Hedestam lab (Corcoran et al. and Fischer et al.) int…
