Biology subjects

Smith, K. G. C.

Publications and source records attributed to Smith, K. G. C..

7 recordsLinked to original sources

bioRxiv2026

Mitigation of imprinted antibody responses in elderly COVID-19 highly vaccinated individuals

SARS-CoV-2 continues to evolve from the Omicron serotype, with BA.2.86 sublineage JN.1 and descendants predominating in 2025-26 and recent emergence of the highly divergent BA.3.2 saltation variant. Elderly individuals continue to be at greatest risk of clinical complications from COVID-19, yet contemporary data on kinetics of immune potency and breadth following multiple vaccinations remain limited in this group. We studied a cohort of forty-three healthy older adults (median age = 85 years, IQR 75-88, 40% female). Using both pseudotyped virus (PVNT) and surrogate virus (SVNT) neutralization-based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high potency neutralization across all studied variants except BA.3.2.2, where titres were around 2-3 fold lower. Waning of serum neutralizing activity was modest between vaccine doses, suggesting sustained immunity following multiple vaccines. Importantly, the half-life of serum neutralization against Wu-1 (179 days) was substantially longer compared to JN.1 subvariants (43.7-70.1days), consistent with imprinted and longer-lived Wu-1-specific responses. Furthermore, half-life for BA.3.2.2 neutralisation was prolonged at 107 days compared to JN.1 subvariants, implicating imprinted ancestral variant targeting antibodies in neutralization of this saltation variant. While absolute neutralization titers remained highest against ancestral Wu-1 at all timepoints due to multiple historical exposures and accumulation, the recall responses after the recent KP.2 vaccine revealed a shift in immunodominance: neutralization against full-length Wu-1 spike was not boosted, whereas all tested JN.1 descendants and BA.3.2.2 showed significant boosts, indicating that immune imprinting against ancestral Wu-1 was partially overcome. These data indicate that in the elderly, protective neutralizing antibody responses against recent VOC can be achieved, with alleviation of immune imprinting and reduction of waned responses through biannual, strain-updated booster vaccines. Imprinted antibodies against ancestral pre Omicron variants may still be relevant for protection against further highly immune evasive variants such as BA.3.2.2, highlighting that careful characterisation of population level COVID-19 humoral immunity is still warranted.

microbiology↗

bioRxiv2023

Fate-mapping lymphocyte clones and their progenies from induced antigen-signals identifies temporospatial behaviours of T cells mediating tolerance

Tissue homeostasis is maintained by the behaviours of lymphocyte clones responding to antigenic triggers in the face of pathogen, environmental, and developmental challenges. Current methodologies for tracking the behaviour of specific lymphocytes identify clones of a defined antigen-receptor--antigen binding affinity. However, lymphocytes can receive antigenic signals from undefined or endogenous antigens, and the strength of each signal, even for the same lymphocyte, varies with accessory signalling, across tissues and across time. We present a novel fate-mapping mouse, that, by tracking lymphocyte clones and their progenies from induced antigen signals, overcomes these hurdles and provides novel insights into the maintenance of tissue homeostasis. We demonstrate the systems use by investigating the maintenance of localised T cell tolerance in tumour immunity. In a murine tumour model, our system reveals how Tregs differentiate to a reversible, tolerance inducing state within the tumour, and recirculate, while CD8+ T cells failing to recirculate, differentiate to an increasingly exhausted, tolerant state in the tumour. These contrasting T cell behaviours provide means by which immunity can tolerate a particular anatomical niche while maintaining systemic clonal protection. Our system can thus explore lymphocyte behaviours that cannot be tracked by previous methods and will therefore provide novel insights into the fundamental mechanisms underlying immunitys role in tissue homeostasis.

immunology↗

bioRxiv2022

Obesity associated with attenuated tissue immune cell responses in COVID-19

Obesity is common and associated with more severe COVID-19, proposed to be in part related to an adipokine-driven pro-inflammatory state. Here we analysed single cell transcriptomes from bronchiolar lavage in three adult cohorts, comparing obese (Ob, body mass index (BMI) >30m2) and non-obese (N-Ob, BMI <30m2). Surprisingly, we found that Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN), IFN{gamma} and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Analysis of peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFN{gamma} response genes, as well as decreased serum IFN, in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFN and IFN{gamma} response genes. Altogether, these findings show blunted tissue immune responses in Ob COVID-19 patients, with clinical implications.

immunology↗

bioRxiv2022

Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

immunology↗

bioRxiv2021

EROS-mediated control of NOX2 and P2X7 biosynthesis

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

immunology↗

bioRxiv2020

Resolving mechanisms of immune-mediated disease in primary CD4 T cells

Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by linkage disequilibrium. To determine whether causal variants could be identified via their functional effects, we adapted a massively-parallel reporter assay for use in primary CD4 T-cells, key effectors of many immune-mediated diseases. Using the results to guide further study, we provide a generalisable framework for resolving disease mechanisms from non-coding associations - illustrated by a locus linked to 6 immune-mediated diseases, where the lead functional variant causally disrupts a super-enhancer within an NF-{kappa}B-driven regulatory circuit, triggering unrestrained T-cell activation.

genetics↗

bioRxiv2018

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of , {beta} and {gamma} chains. Genetic deficiency of the or {gamma} chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) {beta} chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2R{beta} gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2R{beta} and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2R{beta} expression and cytotoxic function. IL-2R{beta} loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2R{beta} expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

immunology↗