Benedict Seddon

Benedict Seddon
Institute of Immunity and Transplantation · Division of Infection and Immunity, UCL

D Phil

About

134
Publications
11,107
Reads
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5,418
Citations
Additional affiliations
November 2013 - present
University College London
Position
  • Reader in Immunology
August 2003 - September 2013
MRC National Institute for Medical Research
Position
  • Programme Leader
October 1998 - August 2003
MRC National Instititute for Medical Research
Position
  • Role of Src family kinases in T cell development and function

Publications

Publications (134)
Preprint
Tissue-resident memory T cells (TRM) protect from repeated infections within organs and barrier sites. The breadth and duration of such protection is defined at minimum by three quantities; the rate at which new TRM are generated from precursors, their rate of self-renewal, and their loss rate through death, egress, or differentiation. Quantifying...
Article
Full-text available
IKK signalling is essential for survival of thymocytes by repressing RIPK1 induced cell death rather than its canonical function of activating NF-κB. The role of IKK signalling in activated T cells is unclear. To investigate this, we analysed activation of IKK2 deficient T cells. While TCR triggering was normal, proliferation and expansion was prof...
Article
Full-text available
Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 effector memory (TEM) and central memory (TCM) T cells in mice appear to shift with age, but it is unclear whether these changes are driv...
Preprint
Foxp3+ Regulatory T cells (Treg) are a subset of CD4+ T cells that play critical functions in maintaining tolerance to self antigens and suppressing autoimmunity, regulating immune responses to pathogens and have a role in the pathophysiology of anti-tumoural immunity. Treg ontogeny is complex since they are generated following recognition of self...
Preprint
Full-text available
Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 ⁺ effector memory (T EM ) and central memory (T CM ) T cells in mice appear to shift with age, but it is unclear whether these changes ar...
Preprint
The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of canonical NF-κB activation. More recently, RIPK1 has also been identified as a phosphorylation target of the IKK complex, resulting in repression of extrinsic cell death pathways. Our previous work shows that normal thymocyte development is exclusively reliant on repression of...
Article
Full-text available
The dynamics of cell populations are frequently studied in vivo using pulse-chase DNA labeling techniques. When combined with mathematical models, the kinetic of label uptake and loss within a population of interest then allows one to estimate rates of cell production and turnover through death or onward differentiation. Here we explore an alternat...
Article
The inhibitor of κB kinase (IKK) complex regulates the activation of the nuclear factor κB (NF-κB) family of transcription factors. In addition, IKK represses extrinsic cell death pathways dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by directly phosphorylating this kinase. Here, we showed that peripheral naïve T cell...
Article
Full-text available
The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of NF-κB activation. More recently, IKK has also been shown to repress RIPK1 dependent extrinsic cell death pathways by directly phosphorylating RIPK1 at serine 25. In T cells, IKK expression is essential for normal development in the thymus, by promoting survival of thymocytes i...
Article
Full-text available
Naive CD4 and CD8 T cells are cornerstones of adaptive immunity, but the dynamics of their establishment early in life and how their kinetics change as they mature following release from the thymus are poorly understood. Further, due to the diverse signals implicated in naive T cell survival, it has been a long-held and conceptually attractive view...
Preprint
Naive CD4 and CD8 T cells are a cornerstone of adaptive immunity, but multiple aspects of their behaviour remain elusive. The dynamics of their establishment early in life, how their kinetics change as they mature following release from the thymus, and the mechanisms by which naive T cells are maintained as thymic activity wanes are all poorly unde...
Preprint
The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of NF-κB activation. In addition, IKK has recently been shown to repress RIPK1 dependent extrinsic cell death pathways by directly phosphorylating RIPK1. Our previous work shows that normal thymopoiesis relies on IKK exclusively for repression of TNF triggered cell death pathways...
Article
Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of T-ALL patients display very high IL7R mRNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mu...
Chapter
Full-text available
The need to maintain cell populations at near-constant sizes – that is, to maintain homeostasis – is ubiquitous in living organisms. Cell populations are usually dynamic, with production through replenishment from a source and division being countered by cell death or differentiation. In the context of T lymphocytes, measuring the relative contribu...
Article
Full-text available
NF-κB signaling is required at multiple stages of T cell development and function. The NF-κB pathway integrates signals from many receptors and involves diverse adapters and kinases. Recent advances demonstrate that kinases controlling NF-κB activation, such as the IKK complex, serve dual independent functions because they also control cell death c...
Article
Full-text available
Follicular mature (FM) and germinal center (GC) B cells underpin humoral immunity, but the dynamics of their generation and maintenance are not clearly defined. Here, we exploited a fate-mapping system in mice that tracks B cells as they develop into peripheral subsets, together with a cell division fate reporter mouse and mathematical models. We f...
Preprint
Follicular mature (FM) and germinal centre (GC) B cells underpin humoral immunity but the dynamics of their generation and maintenance are not clearly defined. Here we exploited a fate-mapping system in mice that tracks B cells as they develop into peripheral subsets, together with a cell division fate reporter mouse and mathematical models. We fin...
Article
Full-text available
In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into...
Article
The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structure...
Article
Full-text available
Laboratory mice develop populations of circulating memory CD4+ T cells in the absence of overt infection. We have previously shown that these populations are replenished from naive precursors at high levels throughout life (Gossel et al., 2017). However, the nature, relative importance and timing of the forces generating these cells remain unclear....
Preprint
Laboratory mice not exposed to overt infections nevertheless develop populations of circulating memory phenotype (MP) CD4+ T cells, presumably in response to environmental, commensal or self-antigens. The relative importance and timing of the forces that generate these populations remain unclear. Here we combine mathematical models with data from s...
Article
Full-text available
NF-κB (nuclear factor κB) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-κB, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-κB transcription, had no impact upon thymocyte development....
Article
Full-text available
The processes regulating peripheral naive T-cell numbers and clonal diversity remain poorly understood. Conceptually, homeostatic mechanisms must fall into the broad categories of neutral (simple random birth–death models), competition (regulation of cell numbers through quorum-sensing, perhaps via limiting shared resources), adaptation (involving...
Data
Detailed description of models and fitting procedures. (PDF)
Data
Data reproduced from Fig 3 of den Braber et al. [8]. (XLSX)
Data
Data from busulfan chimera experiments. (XLSX)
Data
Data reproduced from Figs 2C and 4E in Tsukamoto et al. [14]. (XLSX)
Data
The density-dependent model fails to explain the replacement kinetics in busulfan chimeras (data provided in S2 Data). (PDF)
Data
Simulating the results of thymectomising busulfan chimeric mice under the different model scenarios. (PDF)
Article
Full-text available
IL-7 is essential for the development and homeostasis of T and B lymphocytes and is critical for neonatal lymph node organogenesis because Il7 −/− mice lack normal lymph nodes. Whether IL-7 is a continued requirement for normal lymph node structure and function is unknown. To address this, we ablated IL-7 function in normal adult hosts. Either indu...
Article
This protocol was developed to increase the richness of information available from in vivo T cell proliferation studies. DNA labelling techniques such as BrdU incorporation allow precise control of label administration and withdrawal, so that the division history of a population can be tracked in detail over long timeframes (days-weeks). Ki67 is ex...
Article
This protocol was developed to generate chimeric mice in which T lymphocytes could be stratified by age on the basis of congenic marker expression. The conditioning drug busulfan is used to ablate host haematopoietic stem cells while leaving the peripheral immune system intact. Busulfan treatment is followed by bone marrow transplantation (BMT), wi...
Data
Comparing naive and memory cell numbers and Ki67 expression in busulfan chimeras and wild-type controls (panels B and C) .DOI: http://dx.doi.org/10.7554/eLife.23013.004
Data
Timecourses of the BrdU+ fractions within the Ki67high and Ki67low populations during the BrdU labelling/delabelling experiments.DOI: http://dx.doi.org/10.7554/eLife.23013.014
Data
Ki67 expression in host and donor CD4 TEM and TCM cells in busulfan chimeras 8 weeks post-BMT (panel D).DOI: http://dx.doi.org/10.7554/eLife.23013.017
Data
Data showing stability of both numbers and Ki67 expression of effector memory, central memory and naive CD4 T cells recovered from lymph nodes during BrdU labelling. DOI: http://dx.doi.org/10.7554/eLife.23013.023
Data
Timecourses of infiltration of donor-derived T cells into the naive and memory compartments in busulfan chimeras (panel E).DOI: http://dx.doi.org/10.7554/eLife.23013.005
Data
Timecourses of numbers and chimerism within the naive, effector memory and central memory CD4 T cell compartments in busulfan chimeras (Figure 2 panels B and C, and Figure 2—figure supplement 1).DOI: http://dx.doi.org/10.7554/eLife.23013.007
Data
Source code used to analyse flows between naive, CD4 TEM and CD4 TCM populations.DOI: http://dx.doi.org/10.7554/eLife.23013.008
Data
Source code used to generate and fit models to BrdU/Ki67 timecourses.DOI: http://dx.doi.org/10.7554/eLife.23013.015
Article
Full-text available
Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to the maintenance of memory compartments. Here, we characterise the kinetics and structure of murine C...
Article
Full-text available
NF-κB activation has been implicated at multiple stages of thymic development of T cells, during which it is thought to mediate developmental signals originating from the T cell receptor (TCR). However, the Card11–Bcl10–Malt1 (CBM) complex that is essential for TCR activation of NF-κB in peripheral T cells is not required for thymocyte development....
Article
Full-text available
Immunity to many human and murine gastrointestinal helminth parasites requires interleukin-4 (IL-4)-directed type 2 helper (TH2) differentiation of CD4(+) T cells to elicit type-2 immunity. Despite a good understanding of the inflammatory cascade elicited following helminth infection, the initial source of IL-4 is unclear. Previous studies using th...
Article
Full-text available
Significance T cells are essential components of vertebrate immune systems, but the mechanisms by which they are maintained are still poorly defined. Existing methods infer cell lifetimes and division rates using DNA labeling of dividing cells, but do not resolve heterogeneity in population dynamics well. We present a novel experimental system that...
Article
Interleukin 7 (IL-7) promotes the self-renewing ability of CD4-CD8-double-negative thymocytes by both supporting cell growth and repressing rearrangements of the locus encoding the T cell antigen receptor (TCR).
Article
Full-text available
During positive selection of CD4(+), CD8(+) double positive (DP) thymocytes, expression of the tyrosine kinase Zap70 is subject to developmental regulation. Signalling downstream of T-cell receptor (TCR) induces Zap70 expression, forming a positive feedback circuit. Although previous studies show this circuit is required for generation of CD8 linea...
Article
Full-text available
The developmental pathways of regulatory T cells (Treg) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of Treg development. We find that Treg develop with distinctive kinetics, first appeari...
Article
Full-text available
The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterog...
Article
Full-text available
Survival of naive T cells requires engagement of TCR with self-peptide major histocompatibility Ags. The signaling pathways required to transmit this survival signal are poorly understood. In this study, we asked whether the tyrosine kinase Zap70 is required to transmit survival signals in naive CD8 T cells. In the absence of Zap70 expression, thym...
Article
The number of T Lymphocytes (T cells) in the body is under homeostatic control. At equilibrium, the majority of naive T cells are non-dividing and express low levels of the surface protein CD44. In conditions of T cell deficiency (lymphopenia), naive T cells enter into a proliferative phase, undergoing cell division accompanied by a subtle change i...
Article
Full-text available
TCR signaling plays a central role in directing developmental fates of thymocytes. Current models suggest TCR signal duration directs CD4 versus CD8 lineage development. To investigate the role of TCR signaling during positive selection directly, we switched signaling off in a cohort of selecting thymocytes and followed, in time, their subsequent f...
Article
Full-text available
Significance Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. Our study identifies a role for the Nuclear Factor κ-B (NF-κB) signalling pathway in the control of IL-7 receptor expression by T cells. Following thymic selection, new T cells specifically up-regulate IL-7R even as th...
Conference Paper
Full-text available
Quantifying the rate at which individual cytotoxic T lymphocytes (CTL) can survey and kill target cells is important for deriving ground-up estimates of critical CTL densities required for the control of infections. Estimates of this quantity have been derived from in vivo killing assays, using the relative survival of target and control cells expo...
Data
Fitting the TIM mapping function to various readouts of immune activation derived from the data in Obst et al. [58]. Upper row: Our proposed sigmoid mapping function yielded reasonable descriptions of three readouts of immune activation, all assumed to be proportional to peptide abundance on APC. Lower panel: we show the best fitting functions deri...
Data
Explaining the effect of partial and strong agonists on T selection efficiency. Figure 9 in the main text illustrates how the observations of Cozzo Picca et al. [15] regarding the effect of partial and strong agonists on T selection efficiency can be explained with the two phase model. This model can be extended to include multiple pMHC per encount...
Data
Full-text available
Plausible combinations of parameters of the model. We used discrete combinations of , the maximum number of APC encounters made by a thymocyte, and , the fraction of endogenous peptides that are capable of inducing a TCR signal. Mean (minimum, maximum) values correspond to parameter combinations that described the data within AIC2 of the lowest AIC...
Data
Alternative models of T selection for TCR clonotypes with varying sensitivity to endogenously expressed ovalbumin (OVA) peptide, as used in Lee et al.[14]. In the model (upper panel), each curve represents the distribution of summed signal strengths () for TCRs with varying affinity for endogenously expressed OVA peptide. The probability that the s...
Data
Full-text available
Exploring the relation between relative TIM RNA expression and immune activation. (PDF)
Data
Full-text available
The calculation of the selection probabilities in the model. (PDF)
Data
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Explaining variation in T selection efficiency with TCR affinity. (PDF)
Data
The calculation of the selection probabilities in the two-phase model. (PDF)
Article
Full-text available
Significance Thymocytes express a diverse repertoire of T-cell antigen receptors. Stringent selection processes eliminate autoreactive cells and guide useful thymocytes to develop into CD4 or CD8 lineages. Development always generates more CD4 than CD8 T cells, but it is not understood why. Our study used mathematics to investigate the basis of thi...
Article
Full-text available
Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the...
Article
Full-text available
The production of protective antibody requires effective signalling of naive B cells following encounter with antigen, and the divergence of responding B lymphocytes into distinct lineages. Polarity proteins have recently been proposed as important mediators of both the initial B cell response, and potentially of asymmetric cell division. Here we s...
Article
Full-text available
Lymphopenia induces T cells to undergo cell divisions as part of a homeostatic response mechanism. The clonal response to lymphopenia is extremely diverse, and it is unknown whether this heterogeneity represents distinct mechanisms of cell-cycle control or whether a common mechanism can account for the diversity. We addressed this question by combi...
Article
116 Interleukin 7 (IL-7) and its receptor, a heterodimer constituted by IL-7Rα (hereafter referred to as IL7R) and γc subunits, are essential for normal T-cell development and homeostasis. While it is known for long that IL7R genetic inactivation leads to severe combined immunodeficiency, only recently we and others have found IL7R gain-of-function...
Conference Paper
Full-text available
Purpose/Objective: The increasing prevalence of inflammatory bowel diseases (IBD) in the developed world reinforces the need to understand the mechanisms that lead to onset of inflammation in the gut. Previous work from our lab identified a population of RORgtdependent, IL-23-responsive innate lymphoid cells (ILCs). These could drive inflammation i...