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The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.During homeostasis TH1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this TH1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.

Most vertebrates are infected with one or more herpesviruses and remain so for the rest of their lives. The relationship of immunocompetent healthy host with herpesviruses may sometime be considered as harmonious. However, clinically severe diseases can occur when host immunity is compromised due to aging, during some stress response, co-infections or during neoplastic disease conditions. Discord can also occur during iatrogenic immunosuppression used for controlling graft rejection, in some primary genetic immunodeficiencies as well as when the virus infects a non-native host. In this review, we discuss such issues and their influence on host-herpesvirus interaction.

We investigated the influence of a transient treatment of corticosteroid on CD8 T cells during herpesvirus infection. Dexamethasone, a synthetic corticosteroid, induced apoptosis of naïve and memory CD8 T cells but virus-specific effector cells were spared. CD8 T cell susceptibility was directly correlated with the expression of nr3c1. Both α-(HSV1) and γ-(MHV68) herpesvirus infection expanded CD8 T cells down regulated nr3c1 indicating corticosteroid-mediated effects were not limited to one pathogen or the specific clonotype. Dexamethasone compromised anti-viral immunity to subsequent infections, likely through reductions in the naïve cell pool. Dexamethasone augmented the function and inflammatory tissue homing potential of effector cells via upregulation of CXCR3. Accordingly, an antibody neutralization of CXCR3 diminished dexamethasone-induced migration of CD8 T cells to tissues resulting in increased virus burden. Our study therefore suggests that even a transient corticosteroid therapy influences both ongoing CD8 T cell responses as well as the size of the naïve and memory repertoire.

The strength of the repressive histone H3K27me3 signal varies across silencers. Focusing on regions with unusually strong signals—super-silencers—we show that B-cell super-silencers are initially linked to gene upregulation in development, with target genes highly expressed in stem cells. About 13% of B-cell super-silencers convert to super-enhancers in B-cell lymphoma; 22% of these recur in over half of patients. Genes like BCL6 and BACH2 tied to these conversions are downregulated faster by JQ1, a super-enhancer-disrupting anti-cancer agent. Super-silencers are enriched for B-cell cancer-associated variants—both somatic and germline—and translocation breakpoints, exceeding levels in other regulatory elements like CTCF  binding sites. Over 80% of B-cell lymphoma t(3;14)(q27;q32) translocations fuse BCL6 super-silencers with enhancer-rich regions. Super-silencer repression depends on CpG content: CpG-rich elements block promoter–enhancer contacts; CpG-poor — inhibit looping. These findings highlight super-silencers’ key role in B-cell regulation and suggest their alteration may be a primary factor of B-cell carcinogenesis. In B-cells, super-silencers originally help activate important genes during early development. Later, they switch roles and become powerful silencers in mature B cells. Super-silencers help control gene activity in healthy B-cells, but when they malfunction or mutate, they may drive the development of B-cell cancers. In healthy, mature B cells, super-silencers keep developmental genes switched off to maintain cell identity. When disrupted by mutation or malfunction, these elements can reverse their role and contribute to the development of B-cell cancers.

Low vitamin D levels have been associated with hyperreactive airway diseases (HRADs) such as wheeze-associated lower respiratory tract infections, asthma, and allergic rhinitis in children. Vitamin D insufficiency is a modifiable risk factor for managing recurrent respiratory tract infections. This study aimed to estimate vitamin D levels in HRAD patients and assess their association with HRAD by comparing them to healthy children. This case-control study was conducted over 18 months in the Department of Paediatrics, Guru Gobindsingh Government Hospital, Jamnagar. A total of 200 children (100 cases with HRADs and 100 healthy controls) aged six months to 12 years were enrolled using simple random sampling. Cases included children with ≥2 episodes of wheeze-associated lower respiratory tract infections or asthma. Controls were healthy children who were not taking vitamin D3 supplements attending the immunization clinic. Vitamin D levels were measured using electrochemiluminescence immunoassay (ECLIA). Data on dietary habits, sun exposure, and nutritional status were collected. Chest and wrist X-rays were evaluated. The mean vitamin D level in cases (30.2 ± 17.8 ng/mL) was lower than that of controls (33.6 ± 14.5 ng/mL), with significantly higher odds of deficiency in cases (OR 3.31, p = 0.001). Vitamin D deficiency was associated with younger age, poor nutritional status, limited sun exposure, and low dietary intake of vitamin D-rich foods. Chest X-ray hyperinflation and wrist X-ray findings were significantly linked to vitamin D deficiency. Vitamin D deficiency is significantly associated with HRADs in children. Screening and prophylaxis for vitamin D deficiency, particularly in at-risk groups, may help manage HRADs effectively.

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TG AC8 ) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TG AC8 mice is associated with the activation of inflammation-related signaling pathways. However, the immune response associated with chronic myocardial stress in the TGAC8 mouse remains unexplored. Here we demonstrate that chronic activation of adenylyl cyclase in cardiomyocytes of TG AC8 mice results in activation of cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. All these changes precede the appearance of cardiac fibrosis. We provide evidence indicating that RelA activation in cardiomyocytes with chronic activation of adenylyl cyclase is mediated by calcium-protein Kinase A (PKA) signaling. Using a model of chronic cardiomyocyte stress and accelerated aging, we highlight a novel, calcium/PKA/RelA-dependent connection between cardiomyocyte stress, myocardial inflammation, and systemic inflammation. These findings suggest that RelA-mediated signaling in cardiomyocytes might be an adaptive response to stress that, when chronically activated, ultimately contributes to both cardiac and systemic aging.

We sought to identify and characterize HSV1 specific CD8+ T cells in the experimentally infected zebrafish (zf), a model organism that offers real time tracking of cellular dynamics. We generated a fluorescently labelled class I MHC tetramer of zebrafish using an H-2Kb restricted peptide of gB protein of HSV1 (Uda-HSV1-gB-SSIEFARL-tetramer) for analysing the differentiation of virus-specific CD8+ T cell response. We show that the Uda-SSIEFARL-tetramer+CD8+ T cells rapidly expand in the lymphoid organs and are efficiently recruited to non-lymphoid tissues of HSV1 infected zebrafishes. The expanded cells upregulate effector cytokines; IFN-γ, IL-2, TNF-α and cytolyze SSIEFARL-peptide pulsed targets. Uda-SSIEFARL-tetramer+CD8+ T cells efficiently migrate to the infected tissues as demonstrated by fluorescent microscopy and in vivo imaging. The Uda-SSIEFARL-tetramer+ memory cells are recalled in the response following a secondary infection of zebrafish with HSV1. We, therefore, make a rather intriguing observation that zebrafishes infected with HSV1 generate an efficient CTL response against H-2Kb restricted HSV1-gB-SSIEFARL epitope despite their evolutionary divergence from mice ∼445 million years ago. We also argue that zebrafish could serve as a better accessible model organism for studying in vivo dynamics of virus-specific CD8+ T cells.

The strength of the repressive histone H3 lysine 27 trimethylation modification signal varies drastically at individual silencers. Focusing on cases of an unusually strong repressive signal in regions that we refer to as super-silencers, we demonstrate that the regions that become B-cell super-silencers are originally associated with gene upregulation during development, and their target genes are highly expressed in stem cells, especially during early developmental stages. About 13% of B-cell super-silencers transmute to super-enhancers in B-cell lymphoma and 22% of these conversions recur across more than half of patients. Notably, genes associated with these conversions, like and , are downregulated more swiftly than others when subjected to JQ1, a super-enhancer-disrupting bromodomain and extra-terminal domain inhibitor utilized in cancer chemotherapy. Furthermore, super-silencers are characterized by an over-representation of B-cell-cancer-associated mutations, both somatic and germline, and B-cell-cancer translocation breakpoints. This surpasses the prevalence found in other regulatory elements, such as CTCF binding sites, underlining the crucial role of super-silencers in forming and stabilizing regulatory topologies in standard B cells. For example, over 80% of cases involving the B-cell-lymphoma translocation t(3;14)(q27;q32) fuse super-silencers in the locus with enhancer-rich domains. Finally, we demonstrate that the repressive mechanisms of super-silencers are partially governed by the CpG content in their sequences. While CpG-rich super-silencers often prevent promoters from interacting with enhancers, CpG-depleted super-silencers typically suppress the chromatin looping of nearby enhancers. In summary, our findings accentuate the critical role super-silencers play in the normal function of B-cells, suggesting that sequence mutations and activity modifications in these elements could be primary factors in B-cell carcinogenesis.

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TG AC8 ) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity.BackgroundMice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TG AC8 ) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity.Here we demonstrate that activation of ACVIII in cardiomyocytes results in cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. These changes precede the appearance of cardiac fibrosis. We provide evidence indicating that ACVIII-driven RelA activation in cardiomyocytes is mediated by calcium-Protein Kinase A (PKA) signaling.ResultsHere we demonstrate that activation of ACVIII in cardiomyocytes results in cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. These changes precede the appearance of cardiac fibrosis. We provide evidence indicating that ACVIII-driven RelA activation in cardiomyocytes is mediated by calcium-Protein Kinase A (PKA) signaling.Using a model of chronic cardiomyocyte stress and accelerated aging we highlight a novel, PKA/RelA-dependent connection between cardiomyocyte stress, myocardial para-inflammation and systemic inflammation. These findings point to RelA-mediated signaling in cardiomyocytes and inter-organ communication between the heart and lymphoid organs as novel potential therapeutic targets to reduce age-associated myocardial deterioration.ConclusionsUsing a model of chronic cardiomyocyte stress and accelerated aging we highlight a novel, PKA/RelA-dependent connection between cardiomyocyte stress, myocardial para-inflammation and systemic inflammation. These findings point to RelA-mediated signaling in cardiomyocytes and inter-organ communication between the heart and lymphoid organs as novel potential therapeutic targets to reduce age-associated myocardial deterioration.