Cardiovascular risk factors can spark inflammation by eliciting misdirected responses of intrinsic vascular cells and leukocytes, culminating in lesion initiation, progression, and complication. Soehnlein and Libby review key underlying inflammatory mechanisms in atherosclerosis and discuss how new understanding based on increasingly sophisticated tools has enabled translation to the clinic.

Obesity and its related disorders are now recognized as chronic inflammatory conditions. Donath and Drucker review the mechanisms underlying inflammation in these settings and discuss how understanding the mechanisms whereby Glucagon-like peptide-1 (GLP-1) receptor agonists function may unlock further therapeutic potential in chronic inflammatory diseases.

TCF-1, encoded by Tcf7, supports CD8+ T cell memory and is silenced in effector T cells. Murphy et al. identify two cis-elements required for Blimp1-mediated Tcf7 repression and find that decoupling Tcf7 silencing from effector differentiation is permissive for effector gene expression. Thus, Blimp1 restricts memory differentiation through both Tcf7-dependent and -independent pathways.

The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional state…

Benamar et al. demonstrate that Notch3+ Treg cells are increased in multiple sclerosis and in EAE. They are induced in the gut by microbiota and translocate to the CNS to degenerate into pathogenic Th17 cells. They also outcompete a protective NPY1R+-resident Treg cell population that controls Th1 responses.

Type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation, but the role of Eomes in Tr1 differentiation and function after cell therapy is unclear. Zhang et al. find that Eomes controls the acquisition of regulatory and cytotoxic function in CD4+ T cells that are critical for limiting immune toxicity, while maintaining persistence and tumor control after immunotherapy.

Metabolic stress imposed by the tumor microenvironment (TME) promotes T cell dysfunction and limits antitumor immunity. Alicea Pauneto et al. demonstrate the hypoxia within the TME drives chronic activation of ATF4, which promotes metabolic polarity and cell death of tumor-infiltrating CD8+ T cells (TILs). ATF4 integrates tumor hypoxia and mitochondrial defects in TILs.

Polletti et al. show that in macrophages, ISWI chromatin remodelers preserve nucleosome arrays flanking PU.1-bound sites. ISWI deficiency enabled binding of the transcriptional regulator C/EBPβ to non-myeloid genomic regulatory elements, driving lineage-inappropriate transcription and exaggerated and stimulus-mismatched gene activation. Their findings point to nucleosome phasing as an important regulator of lineage fidelity and immune cell activation.

S. aureus skin colonization is associated with food allergy in atopic dermatitis, but the mechanism of this association is unknown. Das et al. reveal that cutaneous exposure to S. aureus causes a basophil influx into skin-draining lymph nodes that drives a heightened T helper-2 response to simultaneously encountered antigen with increased serum IL-4 concentration, which enhances intestinal permeability, exaggerating oral anaphylaxis.

The term “extrafollicular” is now being used expansively to describe a variety of B cell processes beyond the original use of the term, potentially obscuring important distinct immunological processes. We discuss current uses of the term extrafollicular and propose a framework to help classify these evolving concepts in B cell biology.

While microglial activation is a hallmark in neurodegeneration, the specific role of microglia in disease-related cortical excitability remains unknown. Xie et al. reveal that rod-shaped microglia form in response to early cortical hyperactivity in a mouse model of TDP-43 neurodegeneration. These specialized microglia interact with neuronal dendrites and remodel excitatory inputs, providing a neuroprotective effect.

Triple-negative breast cancer (TNBC) is characterized by high risks of relapse or metastatic disease. Mattavelli et al. identify a chemokine axis that recruits immunosuppressive monocytes to tumor-draining lymph nodes. By co-targeting this recruitment, the TNBC response to immune checkpoint blockade is augmented and metastasis to the lung is reduced.

Integrin CD103 mediates memory T cell tissue residency by binding E-cadherin-expressing epithelial cells, but why CD103 is also expressed on circulating naive CD8+ T cells has been unclear. Li et al. ...

Integrin CD103 mediates memory T cell tissue residency by binding E-cadherin-expressing epithelial cells, but why CD103 is also expressed on circulating naive CD8+ T cells has been unclear. Li et al. report that CD103 facilitates the interaction of naive CD8+ T cells with E-cadherin-expressing dendritic cells that in turn provide cytokine-mediated cues to promote their differentiation into memory-phenotype effector T cells.

Chronic rhinosinusitis (CRS) is driven by poorly understood immune-epithelial crosstalk. Liao et al. present a single-cell and spatial transcriptomic atlas of CRS, revealing how immune and epithelial cells interact to drive tissue remodeling and inflammation. This resource provides insight into disease mechanisms and offers a valuable framework for studying chronic inflammatory disorders of the airway.

Clinical and therapeutic innovation relies on our understanding of the human immune system. Here, investigators discuss current and developing methodologies to study human immunity, and the importance of thoughtful experimental design and sample collection for advancing the frontier of immunology research.