Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization

Eastman, Alison J.; Xu, Jintao; Bermik, Jennifer; Potchen, Nicole; Dekker, Aaron den; Neal, Lori M.; Zhao, Guolei; Malachowski, Antoni; Schaller, Matt; Kunkel, Steven L.; Osterholzer, John J.; Kryczek, Ilona; Olszewski, Michal A.

doi:10.1126/sciadv.aaw9051

Cited by 20 publications

(28 citation statements)

References 76 publications

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“…This is due, at least in part, to a limited understanding of how dysregulated CNS inflammation causes neurological pathology during CM, as well as a lack of reliable biomarkers to separate patients with CM with inadequate versus exaggerated neuroinflammatory responses (11,13,15). The vast majority of mechanistic studies on host defense in cryptococcal infections use murine pulmonary infection models, in which T helper 1 (T H 1)-polarized T cell-mediated responses were shown to be protective and to limit disease pathology (16)(17)(18)(19)(20)(21). The signature T H 1 cytokines, interferon- (IFN-) and tumor necrosis factor- (TNF-), activate fungicidal responses in pulmonary effector phagocytes (monocytes, macrophages, and monocyte-derived dendritic cells), marked by the production of nitric oxide (NO) via inducible NO synthase (iNOS) (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis

Neal

Ganguly

et al. 2020

Sci. Adv.

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Cryptococcal meningoencephalitis (CM) is the major cause of infection-related neurological death, typically seen in immunocompromised patients. However, T cell–driven inflammatory response has been increasingly implicated in lethal central nervous system (CNS) immunopathology in human patients and murine models. Here, we report marked up-regulation of the chemokine receptor CXCR3 axis in human patients and mice with CM. CXCR3 deletion in mice improves survival, diminishes neurological deficits, and limits neuronal damage without suppressing fungal clearance. CD4+ T cell accumulation and TH1 skewing are reduced in the CNS but not spleens of infected CXCR3−/− mice. Adoptive transfer of WT, but not CXCR3−/− CD4+ T cells, into CXCR3−/− mice phenocopies the pathology of infected WT mice. Collectively, we found that CXCR3+CD4+ T cells drive lethal CNS pathology but are not required for fungal clearance during CM. The CXCR3 pathway shows potential as a therapeutic target or for biomarker discovery to limit CNS inflammatory damages.

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Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis

Neal

Ganguly

et al. 2020

Sci. Adv.

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“…Interestingly, results of Menachery et al (2018) revealed a possible association of H3K27me3 global methylation with downregulation of ISG and DNA methylation of antigen presentation gene upon MERS-CoV and H5N1VN1203 [ 66 ]. The possible association of TNF-α and H3K4me3 in the induction of trained innate immunity in monocytes and DC1 antigen presentation and TH1/TH17 immunity upon infection has been described previously [ 67 , 69 ]. Mechanistically, it was observed that an increase in either TNF-α or IFN-γ is sufficient to induce the MLL1 activity which stimulates H3K4 methylation and is required for DC stabilization [ 67 ].…”

Section: Epigenetic Approach Of Coronavirus Immune Evasionmentioning

confidence: 95%

“…HDAC mediates the regulation of non-histone proteins involved in mechanisms crucial for cellular functions like DNA repair, replication, P53 signaling, HIF-1α, STAT3 or p65. HDAC macrophages display a pro-inflammatory function by producing pro-inflammatory cytokines like TNF-α, MCP-1, IL-1α, IL-1β and IFN-γ and are a potential target for HDAC inhibitors [ 69 ]. The role of HDAC2 in modulating the NF-κB activity plays a significant role in the immune evasion strategy of SARS-CoV-2.…”

Section: Epigenetic Approach Of Coronavirus Immune Evasionmentioning

confidence: 99%

An Immune Epigenetic Insight to COVID-19 Infection

et al. 2021

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Severe acute respiratory syndrome coronavirus-2 is a positive-sense RNA virus, a causal agent of ongoing COVID-19 pandemic. ACE2R methylation across three CpG sites (cg04013915, cg08559914, cg03536816) determines the host cell’s entry. It regulates ACE2 expression by controlling the SIRT1 and KDM5B activity. Further, it regulates Type I and III IFN response by modulating H3K27me3 and H3K4me3 histone mark. SARS-CoV-2 protein with bromodomain and protein E mimics bromodomain histones and evades from host immune response. The 2′-O MTases mimics the host’s cap1 structure and plays a vital role in immune evasion through Hsp90-mediated epigenetic process to hijack the infected cells. Although the current review highlighted the critical epigenetic events associated with SARS-CoV-2 immune evasion, the detailed mechanism is yet to be elucidated.

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“…Trained monocytes and macrophages were described essentially by their ability to more efficiently produce cytokines, especially IL-6 and TNFa, upon exposure to unrelated stimuli (29,(34)(35)(36)(37). Other cells from the myeloid lineage, such as DCs (29,38,39) and even neutrophils (40)(41)(42)(43), despite their very short life span, were recently reported to display enhanced innate functions long after the initial stimulation. A burgeoning diversity of neutrophil phenotypes and functionalities are being uncovered, with their capacity to act as APCs a current focus of investigation (44).…”

Section: Trainable Cellsmentioning

confidence: 99%

Optimize Prime/Boost Vaccine Strategies: Trained Immunity as a New Player in the Game

et al. 2021

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Most vaccines require multiple doses to induce long-lasting protective immunity in a high frequency of vaccines, and to ensure strong both individual and herd immunity. Repetitive immunogenic stimulations not only increase the intensity and durability of adaptive immunity, but also influence its quality. Several vaccine parameters are known to influence adaptive immune responses, including notably the number of immunizations, the delay between them, and the delivery sequence of different recombinant vaccine vectors. Furthermore, the initial effector innate immune response is key to activate and modulate B and T cell responses. Optimization of homologous and heterologous prime/boost vaccination strategies requires a thorough understanding of how vaccination history affects memory B and T cell characteristics. This requires deeper knowledge of how innate cells respond to multiple vaccine encounters. Here, we review how innate cells, more particularly those of the myeloid lineage, sense and respond differently to a 1st and a 2nd vaccine dose, both in an extrinsic and intrinsic manner. On one hand, the presence of primary specific antibodies and memory T cells, whose critical properties change with time after priming, provides a distinct environment for innate cells at the time of re-vaccination. On the other hand, innate cells themselves can exert enhanced intrinsic antimicrobial functions, long after initial stimulation, which is referred to as trained immunity. We discuss the potential of trained innate cells to be game-changers in prime/boost vaccine strategies. Their increased functionality in antigen uptake, antigen presentation, migration, and as cytokine producers, could indeed improve the restimulation of primary memory B and T cells and their differentiation into potent secondary memory cells in response to the boost. A better understanding of trained immunity mechanisms will be highly valuable for harnessing the full potential of trained innate cells, to optimize immunization strategies.

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Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization

Cited by 20 publications

References 76 publications

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis

An Immune Epigenetic Insight to COVID-19 Infection

Optimize Prime/Boost Vaccine Strategies: Trained Immunity as a New Player in the Game

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