Eosinophils are now recognized as multifunctional immune cells that contribute to tissue homeostasis, repair, metabolism and host defense in addition to fulfilling their established roles in type 2 immunity and allergic disease. Substantial eosinophil heterogeneity is evident across tissues and inflammatory states, challenging the view that eosinophils are a uniform population of short-lived effector granulocytes. Here we discuss the current understanding of eosinophil development, tissue adaptation and functional specialization across organs and disease contexts. We propose an integrated framework in which eosinophil identity is shaped by four interdependent axes: differentiation and lineage commitment; local environmental cues; time of tissue residence; and inflammatory status. Together, these factors generate eosinophil states that are dynamic, context dependent and continuously tuned to their tissue environment. Viewing eosinophils through this multidimensional lens reframes these cells as adaptable participants in tissue physiology, rather than solely as terminal effectors of type 2 immunity.

Viral infections trigger cellular stress responses, and host stress proteins play key roles in antiviral defense. Here we identify stress-responsive protein arachidonate lipoxygenase-15 (ALOX15) is a critical component of mitochondrial antiviral innate immunity. Loss of Alox15 impairs mitochondrial antiviral signaling (MAVS)-mediated type I interferon production, resulting in increased susceptibility to influenza virus, an effect reversed by adeno-associated virus-mediated lung delivery of Alox15. ALOX15 translocates to mitochondria in response to H1N1 and other RNA viruses (H3N2 and human coronavirus-229E), independent of its enzymatic activity. This mitochondrial localization is also strikingly observed in peripheral blood mononuclear cells from influenza-infected individuals. Mechanistically, ALOX15 is recruited to mitochondria by polymerized MAVS, displacing the deubiquitinase USP19 and sustaining MAVS K63-linked ubiquitination and aggregation. Leveraging these insights, we developed a synergistic ALOX15 regulation-based therapeutic strategy for influenza infection by combining the ALOX15 transcriptional activator songorine with its enzymatic inhibitor PD146176. Together, our findings establish ALOX15 as an essential component of mitochondrial antiviral immunity and a promising host-directed target for antiviral therapy.

Viral persistence refers to the ability of a virus to remain in its host for an extended period. Although most non-retroviral RNA viruses are traditionally known for causing acute, self-limiting infections, accumulating evidence of the detection of viral products long after the infectious virus is cleared suggests that RNA viruses can establish persistent infections. Persistent viral products include replication-competent viral genomes, viral proteins, mutated viruses or non-standard viral genomes. The persistence of viral products entails a continuous interaction with the host and is often associated with prolonged tissue inflammation and chronic disease. Here, we discuss emerging evidence of the persistence of viral products from viruses commonly considered to cause acute infections. We explore the known requirements for virus persistence and the implications for the development of post-acute sequelae and predisposition to chronic inflammatory syndromes.

Exhausted CD8[+] T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8[+] TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8[+] TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8[+] TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8[+] TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.

Within days of exposure to chronic viral infections, activated CD8[+] T cells differentiate into Tcf1[-]Slamf6[lo]Tim3[hi] exhaustion-prone effector T (TEX_EFF) cells or self-renewing Tcf1[+]Slamf6[hi]Tim3[lo] precursor exhausted T (TPEX) cells. Here we showed that early CD8[+] TEX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8[+] TEX_EFF and CD8[+] TPEX cell fates, respectively. Id2 drove CD8[+] TEX_EFF cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8[+] TPEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8[+] TEX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8[+] TEX cell fates and ensuring lineage stability.

Women who have full-term pregnancies have a reduced risk of breast cancer, although the underlying mechanisms are not well understood. Here we show that tissue-resident memory-like T (TRM-like) cells are enriched in the breasts of parous women and mice compared to nulliparous individuals. These cells develop during mid-gestation, persist after lactation and are closely associated with mammary epithelial cells, suggesting dependence on epithelial-derived signals. Impaired alveolar differentiation or a deficiency in epithelial cell-derived cytokines interleukin (IL)-15 and transforming growth factor (TGF)β diminished the expansion of mammary TRM-like cells. Single-cell transcriptomics revealed the expanded TRM-like cells were heterogeneous, comprising CD8αβ[+] and CD8αα[+] subsets. Lineage tracing showed that these TRM-like cells acquire effector functions and contribute to tumor control. Depletion of TRM-like cells abrogated breast tumor protection in parous mice, while enhanced IL-2Rβ signaling-induced TRM-like cells and conferred protection in nulliparous mice. Together, we show a mechanism by which pregnancy can induce anticipatory breast cancer protection in a tissue-specific manner.

Cell migration and strategic positioning within tissues is critical for the rapid mobilization of a T cell response. T cells must remain motile in both lymphoid and nonlymphoid tissues, which vary widely in mechanical properties such as stiffness. Here we showed that activated T cells sensed mechanical cues and responded with changes in cell morphology, nuclear envelope composition and initiation of DNA repair to protect their genomic material from force-mediated damage. Increased mechanical input also drove the transcriptional reprogramming of activated T cells, including changes in many of the core genes shared by tissue-resident memory T cells across diverse tissues, by modulating the expression of the tissue-resident memory T cell-associated transcription factors Klf2, Runx3 and Hic1. Thus, mechanosensing by activated T cells impacted T cell fate, promoting a transcriptional program associated with tissue residency.

Acute myeloid leukemia (AML) is a blood cancer with poor survival outcomes. Acute respiratory failure frequently occurs due to leukemia infiltration of the lungs. Underlying mechanisms remain unexplored and therapeutic interventions remain empiric. Here we map the AML lung microenvironment at spatial and single-cell resolution. We show that extensive remodeling is coupled with inflammation and impaired tissue integrity and function. Steroid treatment significantly reduces AML burden and lung infiltration, improving oxygenation and pulmonary function. As a mechanistic correlate, the S-type lectin Lgals9 is triggered by inflammation and mediates cell-cell interactions within infiltrated lungs. Also, the alarmin IL-33 and its receptor (IL-1RL1) are involved in cell-cell interactions within the leukemic lung microenvironment. Targeting either the Lgals9 or IL-33 axis significantly decreases overall AML burden and lung infiltration through effects on both the immune microenvironment and AML cells. Our studies delineate pulmonary infiltration phenotypes in acute leukemia, enabling new treatment strategies.

The neuroimmune system, an extensive bidirectional communication system between neural cells and immune cells, utilizes evolutionarily conserved molecules, including cytokines, chemokines and trophic factors that participate as mediators in both directions. While the initial discovery of classic immune molecules in the brain was interpreted as neuroinflammation, a broad literature demonstrates their essential roles in cognition during homeostatic brain function. These mechanisms include neural correlates of learning and memory, such as strengthening of neuronal networks and the generation of new neurons and synaptic connections. These processes take place throughout the brain, especially in the hippocampus, a major component of the brain of humans and other vertebrates that consolidates short-term memory into long-term memory and supports spatial navigation. This Review explores recent developments and understanding of immune molecules that orchestrate and participate in molecular mechanisms of memory formation. It also considers their potential efficacy as new targets to treat memory disorders.