Biology subjects

Worthington, A.

Publications and source records attributed to Worthington, A..

7 recordsLinked to original sources

bioRxiv2025

Characterisation of the dual roles of senescent-like T cells that arise during healthy and unhealthy ageing

Ageing is accompanied by progressive remodelling of the immune system, but chronic metabolic disease may accelerate this process and drive qualitatively distinct forms of immune dysfunction. Here, we used type 2 diabetes (T2D) as a model of unhealthy immune ageing to identify a distinct population of CD8 TEMRA cells that accumulates in older individuals with T2D. These cells were highly differentiated, oligoclonally expanded and had shorter telomeres, consistent with an increased replicative history and premature senescence-like state. Unlike conventional TEMRA cells, which can preserve cytotoxic function through acquisition of NK-cell receptors, T2D-associated TEMRA cells showed reduced surface expression of KLRG1, NKG2D and NKG2A together with defective receptor recycling. TGF{beta}1 was elevated in T2D and reproduced several features of this phenotype in vitro, including increased TEMRA differentiation, reduced NK-receptor expression, altered receptor trafficking and induction of p21. Functionally, these cells displayed reduced TCR-triggered degranulation, correlating with impaired cytotoxicity and altered tissue distribution in individuals with T2D. Rather than providing effective immune surveillance, the accumulation of these highly differentiated TEMRA cells with diminished effector capacity may compromise immune function. Together, these findings identify a distinct senescent-like CD8 TEMRA state linking metabolic inflammation to dysregulated T cell differentiation.

immunology↗

bioRxiv2025

Perinatal Nicotine Exposure Disrupts Hematopoietic Stem Cell Development and Elevates Influenza Susceptibility in Adulthood

Tobacco use during pregnancy has many deleterious health consequences for not only the smoking mother, but also on the unborn fetus. Children of smoking mothers are reported to have higher frequency and severity of respiratory diseases later in life; however, the mechanisms driving this increased vulnerability are not clearly understood. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we show that perinatal nicotine exposure (PNE) alters the establishment of HSCs and fetal-derived non-traditional tissue immune cells, with no alterations in circulating immune cell numbers. Suppression of HSCs and lung immune cells persisted for weeks after PNE had ceased. Strikingly, PNE led to increased disease susceptibility and severity upon challenge with influenza A virus in adulthood. This was associated with significant and highly selective alterations in lung immune cells, emphasizing the importance of cellular mechanisms in resilience to infections. Together, these experiments demonstrate that perinatal exposures that have deleterious consequences on hematopoietic establishment can impair immune function for life and identify the cellular mechanisms by which perinatal nicotine exposure predisposes the offspring to a weakened defense against respiratory pathogens. HIGHLIGHTSO_LIPerinatal nicotine exposure (PNE) causes long-term alterations of hematopoiesis C_LIO_LIPNE perturbs hematopoietic stem cell (HSC) development and maintenance C_LIO_LIPNE diminishes the population of fetal-derived tissue-resident alveolar macrophages C_LIO_LIPNE alters cellular mechanisms, exacerbating disease severity later in life C_LIO_LINicotine suppression of central immunity is manifested mechanistically by altered immune cell output C_LI

developmental biology↗

bioRxiv2024

An age-specific platelet differentiation path from hematopoietic stem cells contributes to exacerbated thrombosis

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Hematopoietic stem and progenitor cells continuously give rise to platelets, but their contributions to variable platelet production and activity throughout life remain unclear. Here we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is unique to aging. An unequivocal genetic lineage tracing mouse model demonstrated that this age-specific pathway is progressively propagated over time. Remarkably, the age-specific platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitor cells that that operate in parallel. The age-specific megakaryocyte progenitor population has profoundly enhanced capacity to engraft, expand, and reconstitute platelets, and produces an additional platelet population that exists only in old mice. Consistent with increased thrombotic incidence upon aging, the two pools of co-existing platelets contribute to age-related thrombocytosis and dramatically increased thrombosis in vivo. Upon acute, platelet-specific stress, the age-specific MkPs endowed old mice with superior capacity to rapidly restore platelet counts. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and identify an aging-induced population of functionally enhanced MkPs as a unique source of age-specific platelets. >HIGHLIGHTSO_LIAging leads to two parallel platelet specification paths from HSCs C_LIO_LIThe shortcut platelet pathway is perpetuated by highly expansive MkPs unique to aging C_LIO_LIThe age-specific differentiation path contributes to thrombosis and platelet hyperreactivity C_LIO_LIAge-specific MkPs serve as potent first responders to acute platelet loss C_LI

cell biology↗

bioRxiv2022

Helicobacter chronic stage inflammation undergoes fluctuations that are altered in tlpA mutants

Helicobacter pylori colonizes half of the worlds population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an eight month mouse infection time course and comparison of wild type and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from wild type at some time points. tlpA mutants have equivalent total and gland colonization at late stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to WT. Our results suggest the chronic inflammation setting is dynamic, and may be influenced by colonization properties of early infection. ImportanceHelicobacter pylori established chronic infection in half of the worlds population. This infection initiates during childhood, and leads to later life gastric diseases including gastritis, peptic ulcers, and gastric cancer. These diseases are driven by host inflammation, with more severe inflammation leading to more severe disease. It is not fully understood how H. pylori controls inflammation. In this work, we used an H. pylori mouse infection model and characterized inflammation and colonization of wild-type H. pylori and a mutant that was known to cause elevated inflammation. We found that inflammation in the chronic stage undergoes surprising fluctuations, with related changes in Th17 numbers. H. pylori tlpA mutants caused offset inflammation dynamics, suggesting that H. pylori infection underlies this dynamism. Although there were not colonization dynamics at the time of inflammation fluctuations, there were differences between WT and tlpA mutant colonization at early time points. Our results suggest the chronic inflammation setting is more dynamic than previously thought and may be influenced by colonization properties of early infection.

microbiology↗

bioRxiv2021

Megakaryocyte Progenitor Cell Function is Enhanced Upon Aging Despite the Functional Decline of Aged Hematopoietic Stem Cells

Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. While young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared to young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging. HIGHLIGHTSO_LIFrequencies and total cell numbers of HSCs and MkPs were increased upon aging C_LIO_LIReconstitution deficit by old HSCs was observed by chimerism and absolute cell numbers C_LIO_LIYoung HSCs did not have competitive advantage over old HSCs in aged recipient mice C_LIO_LIOld MkPs display remarkable capacity to engraft, expand, and reconstitute platelets C_LIO_LIAging is associated with changes in MkP genome-wide expression signatures C_LI

cell biology↗

bioRxiv2020

Interleukin 7 receptor (IL7R) is required for myeloid cell homeostasis and reconstitution by hematopoietic stem cells

Respiratory diseases are a leading cause of death worldwide, with highly varied vulnerability to disease between individuals. The underlying reasons of disease susceptibility are unknown, but often include a variable immune response in lungs. Recently, we identified a surprising novel role of the interleukin 7 receptor (IL7R), a primarily lymphoid-associated regulator, in fetal-specified, lung-resident macrophage development. Here, we report that traditional, hematopoietic stem cell-derived myeloid cells in the adult lung, peripheral blood, and bone marrow also depend on IL7R expression. Using single and double germline knockout models, we found that eosinophil numbers were reduced upon deletion of IL7R. We then employed two Cre recombinase models in lineage tracing experiments to test whether these cells developed through an IL7R+ pathway. Despite the impact of IL7R deletion, IL7R-Cre labeled only a minimal fraction of eosinophils. We therefore examined the intrinsic versus extrinsic requirement for IL7R in the production of eosinophils using reciprocal hematopoietic stem cell transplantation assays. These assays revealed that extrinsic, but not eosinophil-intrinsic, IL7R is required for eosinophil reconstitution by HSCs in the adult lung. To determine which external factors may be influencing eosinophil development and survival, we performed a cytokine array analysis between wild-type and IL7R-deficient mice and found several differentially regulated proteins. These findings expand upon our previous publication that IL7R is required not only for proper lymphoid cell development and homeostasis, but also for myeloid cell homeostasis in tissues. HighlightsO_LILoss of IL7R resulted in significantly fewer eosinophils in adult mice C_LIO_LIIL7R-Cre lineage tracing revealed minimal labeling of eosinophils C_LIO_LIIL7R-deficient HSCs robustly reconstituted eosinophils in a WT host C_LIO_LIWT HSCs failed to fully reconstitute eosinophils in IL7R-/- hosts C_LIO_LISeveral cytokines are differentially expressed in WT and IL7R-deficient mice C_LI

immunology↗

bioRxiv2019

The lymphoid-associated interleukin 7 receptor (IL-7R) regulates tissue resident macrophage development

The discovery of a fetal origin for tissue-resident macrophages (trMacs) has inspired an intense search for the mechanisms underlying their development. Here, we performed in vivo lineage tracing of cells with an expression history of IL-7R, a marker exclusively associated with the lymphoid lineage in adult hematopoiesis. Surprisingly, we found that IL7R-Cre labeled fetal-derived, adult trMacs. Labeling was almost complete in some tissues and partial in other organs. The putative progenitors of trMacs, yolk sac (YS) erythromyeloid progenitors (EMPs), did not express IL-7R, and YS hematopoiesis was unperturbed in IL-7R-deficient mice. In contrast, tracking of IL-7R message levels, surface protein expression, and IL7R-Cre-mediated labeling across fetal development revealed dynamic regulation of IL-7R mRNA expression and rapid upregulation of IL-7R surface protein upon transition from monocyte to macrophage within fetal tissues. Fetal liver monocyte differentiation in vitro produced IL-7R+ macrophages, supporting a direct progenitor-progeny relationship. Additionally, blockade of IL-7R function during late gestation specifically impaired the establishment of fetal-derived tissue macrophages in vivo. These data provide evidence for a distinct function of IL-7R in fetal myelopoiesis and identify IL-7R as a novel regulator of tissue-resident macrophage development.

immunology↗