The authors present a framework for the selection of immune aging biomarkers suitable for clinical trials in geroscience, alongside a translational roadmap for biomarker development to support the nex...

BTNL3 and BTNL8 are butyrophilin-like receptors that selectively regulate intestinal Vγ4+ T cells, yet the underlying activation mechanism has remained elusive. Dong et al. reveal that BTNL3-BTNL8 forms an antigen-independent tetramer that drives γδ TCR dimerization and activation, providing a structural basis for tissue-specific immune surveillance.

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 transcription factors cooperate with AP-1/ATF, C/EBP, and PU.1 to drive a lysosome-dependent program within microglia that is shared across neurodegeneration models and Alzheimer’s disease.

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 functional remodeling of microglia and macrophages, including in the context of progranulin deficiency. Their findings connect lysosomal function with microglial state.

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 tumor control by uniquely priming tumor-specific cytotoxic T lymphocytes (CTLs), sustaining their function and enabling responses to immunotherapy.

BTNL3 and BTNL8 are butyrophilin-like receptors that selectively regulate intestinal Vγ4+ T cells, yet the underlying activation mechanism has remained elusive. Dong et al. reveal that BTNL3-BTNL8 for...

Splenic macrophages adapt to malaria through subset-specific remodeling and inter-macrophage communication. Using fate mapping, single-cell transcriptomics, and genetic perturbation, Mauel et al. show that red pulp macrophages (RPMs) and marginal metallophilic macrophages (MMMs) are predominantly yolk sac derived. They identify a CD163high iron-recycling RPM subset that is lost after malaria and find that stress response factor GDF15-dependent signaling supports MMM maintenance.

SARS-CoV-2 encodes a viral deISGylase called PLpro, but its physiological functions and direct substrates remain elusive. Using a deISGylation-activity-ablated recombinant SARS-CoV-2, Zhu et al. show that deISGylation activity is required for innate immune evasion and, furthermore, relieves metabolic restriction of viral replication by modulating the activity of key enzymes in glycolysis, the pentose phosphate pathway, and redox homeostasis.

The meninges play a key role in central nervous system (CNS) inflammation and autoimmunity, but the mechanisms remain unclear. Huang et al. find that group 2 innate lymphoid cells (ILC2s) accumulate in the dura during neuroinflammation, where they activate and expand myelin-reactive T cells, thereby augmenting neuroinflammation and CNS demyelination. Conditional deletion of H2-Ab1 in ILC2s diminishes neuroinflammation and CNS demyelination, highlighting ILC2s as a potential therapeutic target for restricting neuroinflammation.

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 receptor function. Their study explains how IL-23 locks Th17 cells into an inflammatory disease-promoting state and provides a mechanism that explains steroid resistance in Th17 cells.

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 by which it maintains homeostasis in Th17 cells. They find that TGF-β1 can reverse the glucocorticoid resistance exhibited by both murine and human inflammatory Th17 cells.

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 antibodies work together to block parasite invasion. These antibodies rigidify the extended protein “tail,” thus exposing previously inaccessible epitopes. These insights will aid in next-generation vaccine design.

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-derived bacterial niches in the T cell zone that evade recognition and promote persistence.

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 formation in response to high antigen exposure, as seen in chronic infection.

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 human fragment. B cells in knock-in mice undergo class switching and recombination, enabling modular, customizable humanization of additional loci.

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 proliferation. MEK inhibition restores proliferative capacity and maintains a progenitor-like exhausted T cell state that can respond to immune checkpoint blockade.

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 STING acts as a common sensor of diverse bacteria, capable of detecting a broad array of CDN species, including pyrimidine-based CDNs.

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-presenting and checkpoint-regulatory states to T cell-clearing programs, shaping local T cell responses in the brain.

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 distribution by preferentially sensitizing cancer cells to cytotoxic lymphocytes in stiff contexts, such as the bone.

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 generation, phenotype, and antigen-presenting cell dependence, establishing TCR specificity as a primary organizer of peripheral immune tolerance.

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-immune circuits in cancer.

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 B cells, exploring the biochemistry, function, and potential application of the FGL1/TACI interaction in lupus-like autoimmune disease.

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 functional remodeling of microglia and macrophages, including in the context of progranulin deficiency. Their findings connect lysosomal function with microglial state.

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 transcription factors cooperate with AP-1/ATF, C/EBP, and PU.1 to drive a lysosome-dependent program within microglia that is shared across neurodegeneration models and Alzheimer’s disease.

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 tumor control by uniquely priming tumor-specific cytotoxic T lymphocytes (CTLs), sustaining their function and enabling responses to immunotherapy.

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 directly into mouse zygotes by CRISPR-mediated homology-directed repair, generating functional humanized antibody mice in weeks rather than years.

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 dietary antigens to define the rules governing peripheral Treg cell differentiation.

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, whereas MEK inhibition maintains progenitor-like T cells.

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 program that underlies disease-associated microglial states, thereby connecting lysosomal dysfunction with transcriptional regulation in microglia.

Neurogenic inflammation is an important component of cutaneous immunity, yet the mechanism remains incompletely defined. Chen et al. found that the neuropeptide substance P activates mast cell release of the chemokine CCL2 to form dermal aggregates of dendritic cells that are then efficiently activated by a second neuropeptide, CGRP⍺. Thus, initiation of neurogenic inflammation is a dynamic, multi-step process.

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-associated adaptive ER programs that couple organelle expansion with PNAd biosynthesis to drive HEV specialization and reveal conserved secretory programs shared with intestinal goblet cells.

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 shields melanocytes from T cells, limiting autoimmune melanocyte destruction and potentially enabling early melanoma immune escape.

(Immunity 25, 237–247; August 2006)

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 and noncanonical autophagy processes in the form of membrane atg8ylation as an overarching principle affecting multiple immunological processes.

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 found that Gα13-Arhgef1 signaling guides CD8+ IEL migration and villous positioning, enabling TGF-β- and IL-15-dependent maturation and survival.