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Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow–derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)– and extracellular signal–regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α–dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage–specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α–specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype–specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH. Editor's summary: Abberant hepatic macrophage activity has been implicated in NASH development, but the mechanism of this immune dysregulation is unclear. Jeelani et al. show that a hypoxia-inducible factor, HIF-2α, promotes differential effects on macrophage subpopulations during NASH in obesity. HIF-2α suppressed the growth and function of endogenous liver macrophages (Kupffer cells) but increased the proinflammatory activation of the myeloid-derived macrophages that are subsequently recruited to the liver and that start to replace the Kupffer cells. HIF-2α–specific approaches in a murine NASH model and human organoids suggested that this disease biology may be therapeutically targetable. —Catherine Charneski [ABSTRACT FROM AUTHOR]

SARS-CoV-2-reactive T cells are detected in some healthy unexposed individuals. Human studies indicate these T cells could be elicited by the common cold coronavirus OC43. To directly test this assumption and define the role of OC43-elicited T cells that are cross-reactive with SARS-CoV-2, we develop a model of sequential infections with OC43 followed by SARS-CoV-2 in HLA-B*0702 and HLA-DRB1*0101 Ifnar1−/− transgenic mice. We find that OC43 infection can elicit polyfunctional CD8+ and CD4+ effector T cells that cross-react with SARS-CoV-2 peptides. Furthermore, pre-exposure to OC43 reduces subsequent SARS-CoV-2 infection and disease in the lung for a short-term in HLA-DRB1*0101 Ifnar1−/− transgenic mice, and a longer-term in HLA-B*0702 Ifnar1−/− transgenic mice. Depletion of CD4+ T cells in HLA-DRB1*0101 Ifnar1−/− transgenic mice with prior OC43 exposure results in increased viral burden in the lung but no change in virus-induced lung damage following infection with SARS-CoV-2 (versus CD4+ T cell-sufficient mice), demonstrating that the OC43-elicited SARS-CoV-2 cross-reactive T cell-mediated cross-protection against SARS-CoV-2 is partially dependent on CD4+ T cells. These findings contribute to our understanding of the origin of pre-existing SARS-CoV-2-reactive T cells and their effects on SARS-CoV-2 clinical outcomes, and also carry implications for development of broadly protective betacoronavirus vaccines. The origin of SARS-CoV-2 cross-reactive T cells in unexposed humans is unclear. Here, the authors use HLA transgenic mouse models of sequential infections with human coronavirus OC43 and SARSCoV-2 and show that OC43 elicits cross-protective immunity against SARS-CoV-2, which partially depends on CD4 + T cells. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor (TNF) is a pleiotropic cytokine that plays a critical role in the pathogenesis of immune-mediated diseases including inflammatory bowel disease (IBD). The stability of its mRNA transcript, determined in part by destabilizing sequences in its AAUU repeats (ARE) gene region, is an important regulator of its tissue and systemic levels. A deletion in the ARE region of the gene resulted in IBD and arthritis in mice and pigs, supporting a critical role for the cytokine in human IBD and several human arthritides. A mutation in the same area of the mouse genome by Genentech scientists (T.Y., M.K.) resulted in a similar but not identical phenotype., Methods: Here, we compare histopathological, cellular, and molecular features of the strains and propose reasons for their distinct phenotypes. First, while homozygous TNFΔARE mice develop severe arthritis and die after weaning, homozygous Genentech TNFΔARE (ΔG/ΔG) mice have normal lifespans, and males are often fertile., Results: We found that while the ileitic phenotype had peaked at 12 weeks of age in all mice, colitis progressed mostly after 20 weeks of age in heterozygous mice. Their variably penetrant arthritic phenotype progressed mostly after 20 weeks, also in heterozygous mice from both strains. There was expansion of central memory T and B cells in lymphoid organs of TNF-overproducing strains and their transcriptional profile shared well-known pathogenetic pathways with human IBD. Finally, we found differences in the mutated sequences within the ARE regions of the TNF gene and in their microbiota composition and genetic background. These differences likely explain their phenotypic differences., Conclusions: In summary, we describe a different strain of TNF-overproducing mice with an overlapping, yet not identical phenotype, which may have differential applications than the original strain., (© The Author(s) 2025. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: T cell mediated immunity is reported to play a pathogenic role in cardiac allograft vasculopathy (CAV) in heart transplant (HTx) patients. However, peripheral blood CD8 + T cells have not been previously characterized in CAV. This study aimed to identify potentially pathogenic circulating CD8 + T cell populations in high grade CAV patients using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)., Methods: Peripheral blood mononuclear cells (PBMC) collected from International Society for Heart and Lung Transplant (ISHLT) grade 2 or 3 CAV (high grade CAV; n=6) and normal HTx (n=12) patients were analyzed using CITE-seq and VDJ-seq. Key findings were validated by flow cytometry in an independent patient cohort of age-matched CAV (n=11) patients, normal HTx (n=12) patients and healthy donor subjects (n=11)., Results: Among the seven peripheral CD8 + T cell clusters, high grade CAV patients demonstrated a significantly higher proportion of the CD38 + HLA-DR + CD8 + effector memory T (Tem) cell cluster compared to normal HTx patients (median 6.2% vs 2.9%, p=0.01). CD38 + HLA-DR + CD8 + Tem cells showed clonal expansion, activated interferon-γ (IFNG) signaling and enhanced cytotoxicity with granzyme B (GZMB) and perforin (PRF) overexpression. Significantly higher proportion of the proinflammatory and cytotoxic CD38 + HLA-DR + CD8 + Tem cell cluster in high grade CAV compared to normal HTx patients was validated by flow cytometry. There was significantly increased clonal expansion of peripheral CD8 + T cells in high grade CAV compared to normal HTx patients (median Shannon index = 4.4 vs 6.1, p=0.03). CITE-seq identified LAIR2 as a potential biomarker for identifying high grade CAV patients as increased expression was found in CD38 + HLA-DR + CD8 + Tem cells. Plasma LAIR2 was significantly elevated in the high grade CAV (n=20) compared to normal HTx patients (n=20; 16.0 pg/mL vs 70.3 pg/mL, p=0.02)., Conclusions: We discovered and validated circulating CD38 + HLA-DR + CD8 + Tem cells to be significantly increased in high grade CAV compared to normal HTx patients. The proinflammatory and cytotoxic phenotype of this CD8 + T cell cluster suggest its potential pathogenic role in human CAV., Clinical Perspective: What is new?: This is the first study to identify clonal expansion of circulating CD38 + HLA-DR + effector memory CD8 + T cells in human cardiac allograft vasculopathy. CD38 + HLA-DR + effector memory CD8 + T cells possess both proinflammatory and cytotoxic characteristics, suggesting their potential pathogenic role in human cardiac allograft vasculopathy. LAIR2 is a potential signature gene of CD38 + HLA-DR + effector memory CD8 + T cells. What are the clinical implications?: Circulating CD38 + HLA-DR + effector memory CD8 + T cells and plasma LAIR2 protein are potential early biomarkers of cardiac allograft vasculopathy. Evaluation of CD38 + HLA-DR + effector memory CD8 + T cells in longitudinal studies may reveal how this T cell cluster contributes to the development of human cardiac allograft vasculopathy. Inhibiting the expansion of CD38 + HLA-DR + effector memory CD8 + T cells and/or the LAIR2 pathway may become important therapeutic targets for prevention and treatment of human cardiac allograft vasculopathy.