T cell immunoglobulin and mucin domain–containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys 296 ). Palmitoylation stabilized TIM-3 by preventing

NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including

LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson’s disease and Crohn’s disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson’s disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction

Endogenous retroviruses (ERVs), comprising a substantial portion of the vertebrate genome, are remnants of ancient genetic invaders. ERVs with near-intact coding potential reactivate in B cell–deficient mice. To study how B cells contribute to host anti-ERV immunity, we used an antigen-baiting strategy to enrich B cells reactive to ERV surface antigens. We identified ERV-reactive B-1 cells expressing

OX40L-CAR-Tregs show promise for treating autoimmunity and transplantation rejection.

Identity confusion has emerged in the field of monocyte research with the identification of monocyte-like “doppelgänger” populations that exhibit phenotypical traits of classical monocytes but seem to vary in their origin, function, or migration behavior.

In adults, liver-resident macrophages, or Kupffer cells (KCs), reside in the sinusoids and sterilize circulating blood by capturing rapidly flowing microbes. We developed quantitative intravital imaging of 1-day-old mice combined with transcriptomics, genetic manipulation, and in vivo infection assays to interrogate increased susceptibility of newborns to bloodstream infections. Whereas 1-day-old KCs

Conventional dendritic cells (cDCs) generate protective cytotoxic T lymphocyte (CTL) responses against extracellular pathogens and tumors. This is achieved through a process known as cross-presentation (XP), and, despite its biological importance, the mechanism(s) driving XP remains unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein L 7C (APOL7C) is up-regulated in

TP53 mutation triggers IL-34 secretion by cancer stem cells, reprogramming macrophages to suppress T cells and promote tumor immune escape.

Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A–positive

CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor

Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin

Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were

Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP)

Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)–E–restricted CD8 + T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors

Dendritic cells sense confinement in the environment to induce migration in the absence of typical inflammatory stimuli.

Patients with autoimmune disease have exhausted antigen-specific T cells that remain capable of B cell support.

Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)–based single-cell transcriptomics

X chromosome inactivation (XCI) balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of X-inactive specific transcript (Xist) RNA and heterochromatic modifications on the inactive X chromosome (Xi), which are involved in maintenance of XCI, and these modifications return to the Xi after stimulation. Here, we examined allele-specific gene expression and epigenomic

The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating

Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8 + T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8 + T cell clones from the blood

The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of

Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (T H 1) cells selectively developed mitochondrial stress and DNA damage that

Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot

Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4 + T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II–negative cancer cells. The 11 most common tetramer-sorted

Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8 + T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population

Multi-omic analysis deciphers the impact of cell-intrinsic and systemic metabolomes on dengue vaccination immunogenicity.

IL-10 autoantibodies are detected in two patients with severe inflammatory bowel disease.

Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE

Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor–matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations:

HIV envelope immunogen designed to activate germline B cell precursors of CD4 binding site-specific neutralizing antibodies shows promise in monkeys.

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in

Adolescents are a growing population of people living with HIV. The period between weaning and sexual debut presents a low-risk window for HIV acquisition, making early childhood an ideal time for implementing an immunization regimen. Because the elicitation of broadly neutralizing antibodies (bnAbs) is critical for an effective HIV vaccine, our goal was to assess the ability of a bnAb B cell lineage–designed

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of

Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1 , the rate-limiting enzyme in BH4 synthesis

How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (T H 17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of T H 17 and T H 22 cell responses to commensal and pathogenic bacteria

Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and

The Aedes aegypti mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes

Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell–dependent survival

The severe acute respiratory syndrome coronavirus 2 variant JN.1 recently emerged as the dominant variant despite having only one amino acid change on the spike (S) protein receptor binding domain (RBD) compared with the ancestral BA.2.86, which never represented more than 5% of global variants. To define at the molecular level the JN.1 ability to spread globally, we interrogated a panel of 899 neutralizing

Virus and T cell inflammation persist in the tissues of patients with Long Covid.

Programmed death-ligand 1 interacts with fungal ribosomal Rpl20b in phagosomes and induces interleukin-10 secretion.

The lung is constantly exposed to airborne pathogens and particles that can cause alveolar damage. Hence, appropriate repair responses are essential for gas exchange and life. Here, we deciphered the spatiotemporal trajectory and function of an atypical population of macrophages after lung injury. Post–influenza A virus (IAV) infection, short-lived monocyte-derived Ly6G-expressing macrophages (Ly6G

Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection—and they are Ly6G positive (see related Research Article by Ruscitti et al. ).

Aberrant activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity

Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE + murine thymic epithelial

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics

Regulatory T cells (T regs ) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident T regs and group 2 innate lymphoid cells (ILC2s); however, how T regs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of T reg function. Using spatial

Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)–expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell

Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.

αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express

Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.