bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.06.05.136390

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado, M.·Andrada, E.·Liebana, R.·Lopez-Santalla, M.·Merida, I.
View original source ↗Export metadata ↓

Abstract

Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase {zeta} (DGK{zeta}) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKC{theta}/NF{kappa}B pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGK{zeta}-/- mice showed increased numbers of activated T cells in BM, together with a significant increase in IFN{gamma} as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGK{zeta}-/- mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGK{zeta} expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGK{zeta} expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGK{zeta} deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development. Key pointsO_LIDGK{zeta}-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFN{gamma} and lytic enzymes. C_LIO_LIDGK{zeta} loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. C_LI Visual abstract O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/136390v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d485b2org.highwire.dtl.DTLVardef@9599c1org.highwire.dtl.DTLVardef@1a17842org.highwire.dtl.DTLVardef@1de640d_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Martin-Salgado, M., Andrada, E., Liebana, R., Lopez-Santalla, M., Merida, I.. 2020-06-06. Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice. https://doi.org/10.1101/2020.06.05.136390

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Systemic TLR7 agonism moderates disease severity in acute DSS-induced colitis in mice

Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA, studied for its antiviral and pro-inflammatory functions. Its role in intestinal inflammation is undefined, and no approved or clinical-stage therapy for inflammatory bowel disease (IBD) engages this pathway. Here we report that systemic administration of the reference TLR7 agonist GS-9620 (vesatolimod) moderates disease severity in acute dextran sodium sulfate (DSS)-induced colitis in mice. GS-9620-treated mice lost less weight, had lower Disease Activity Index scores, and were protected from DSS-induced colon shortening. Immunophenotyping of the spleen showed reduced Th17 and Tr17 populations and an increased proportion of regulatory T cells. These findings indicate that pharmacological TLR7 agonism is not merely tolerated in the inflamed intestine but is associated with a shift of the systemic immune compartment toward a regulatory phenotype. The results identify TLR7 as a candidate disease-moderating target in IBD and motivate direct tests of causality, route and chronic-disease relevance.

immunology↗
bioRxiv2026

ATF3 Preserves Macrophage Cholesterol Homeostasis during Metabolic Stress

Background: Macrophages must coordinate immune activation with maintenance of cellular cholesterol homeostasis, yet the transcriptional mechanisms integrating these processes remain incompletely understood. Activating transcription factor 3 (ATF3) suppresses inflammatory and interferon responses and has been implicated in macrophage lipid metabolism, suggesting a role in coordinating immune and sterol-responsive transcriptional programs. Methods: Wild-type and ATF3-deficient bone marrow-derived macrophages were analyzed by bulk RNA sequencing following Toll-like receptor stimulation and under conditions of sterol loading or depletion. Cholesterol content, cytokine production, and sterol-responsive gene expression were quantified. Human metabolic dysfunction-associated steatotic liver disease (MASLD) datasets and Kupffer cell-specific ATF3 knockout mice were used to assess disease relevance in vivo. Results: ATF3 deficiency enhanced inflammatory and interferon-responsive transcriptional programs while suppressing a sterol-responsive gene module enriched for SREBP2 target genes. This phenotype was conserved across diverse Toll-like receptor stimuli and accompanied by persistent Ch25h upregulation. Despite exhibiting elevated cellular cholesterol, ATF3-deficient macrophages retained transcriptional responsiveness to sterol loading and depletion while demonstrating reduced induction of SREBP2-dependent genes across conditions. IFNAR blockade reduced interferon-responsive gene expression but did not normalize Ch25h or sterol-responsive gene expression. In contrast, CRISPR-mediated reduction of Ch25h partially restored sterol-responsive gene expression in inflammatory ATF3-deficient macrophages. In human MASLD, hepatic ATF3 expression positively correlated with disease severity. In mice, ATF3 was preferentially induced in Kupffer cells during metabolic stress, and Kupffer cell-specific deletion of ATF3 increased liver injury and Kupffer cell lipid accumulation. Conclusions: ATF3 supports sterol-responsive transcriptional programs while restraining inflammatory activation in macrophages. ATF3 loss results in elevated cellular cholesterol, impaired SREBP2-dependent gene expression, and persistent derepression of Ch25h, which contributes to but does not fully explain the sterol phenotype. These findings identify ATF3 as a coordinator of macrophage adaptation to inflammatory and metabolic stress and support a protective role for Kupffer cell ATF3 during metabolic liver disease.

immunology↗
bioRxiv2026

Circulating CD4 regulatory T cells are broadly preserved in Parkinson's disease despite altered HELIOS expression

Background Regulatory T cells (Tregs) are an important component of adaptive immune regulation and have been implicated in Parkinson's disease (PD), with previous studies suggesting altered Treg proportions, phenotype and, in some cases, function. However, existing studies have been limited by variable phenotyping approaches and a lack of detailed functional assessment. Given the growing interest in Tregs as potential therapies in PD, better understanding of their phenotype and function in the disease is important. Methods Circulating FOXP3+ Tregs were characterised in individuals with PD and age-matched healthy controls (HC) using a 24-colour spectral flow cytometry panel. Treg suppressive function was assessed by their ability to inhibit proliferation and cytokine production by polyclonally stimulated autologous T effector cells in vitro. Treg lineage stability was assessed by analysis of FOXP3 TSDR demethylation. Results The proportions and phenotypic characteristics of circulating CD4 Tregs were broadly similar between individuals with PD and HCs, as were Treg suppressive function and FOXP3 TSDR demethylation. However, naive CD4 Tregs from individuals with PD showed reduced HELIOS expression, with a similar but non-significant trend in FOXP3 expression. Reduced HELIOS expression was also observed in the CD8 naive Treg compartment. Conclusions Major quantitative or functional abnormalities in circulating Tregs do not appear to be a dominant feature PD. However, reduced HELIOS expression in naive Tregs suggests more subtle phenotypic alterations that warrant further investigation. The broadly preserved suppressive function is reassuring for therapeutic approaches aimed at increasing Treg numbers, although it will be important to establish that expanded Tregs retain a stable phenotype and suppressive function in inflammatory and tissue environments.

immunology↗