Dr Natalie Riddell


Lecturer in Immunology and Ageing
BSc, PhD
+44 (0)1483 686475
12 AY 02
9am - 5pm, Mon-Fri

Academic and research departments

School of Biosciences and Medicine.

Biography

Biography

2017 (Jan) Lecturer in Immunology and Ageing, School of Biosciences and Medicine, University of Surrey, Guildford, UK

2010-2017 Senior Postdoctoral Research Associate, Division of Infection and Immunity, UCL, UK

2006-2010 PhD Candidate, School of Sport and Exercise Sciences, University of Birmingham, UK

Research interests

My research is focused on understanding endocrine regulation of the immune system and how the immune system changes with age, with a particular focus on T cell immunology. Senescence of the immune system is believed to contribute to immune function decline with age, resulting in increased illness and infection in older individuals. As the proportion of over 65 year olds in the UK is expected to increase to >25% of the population by 2030, there is an urgent need to understand how the immune system changes with ageing, why these changes occur and, importantly, how we may intervene to reverse of prevent loss of immune function in the elderly.

Every-day physiological and psychological stressors can greatly affect T cell immunity, and therefore our health in general. The two main mediators of this stress response are the hormones adrenaline and cortisol, which are both important regulators of T cell immunity and the immune system in general. These hormones modulate almost every aspect of T cell immunity, including the anatomical distribution of cells, and cell functions such as, cytokine production. Disruptions of normal circadian rhythmicity of adrenaline and cortisol secretion, as is seen in shift workers and during psychological stress, can thus have profound effects on T cell immunity and this is particularly true in elderly individuals. Furthermore, prolonged stress has been found to cause premature and accelerated ageing of the immune system.

Using a combination of human in-vivo and in-vitro systems my research aims to identifying the immune alterations brought about by endocrine control of T cell immunity and the cellular mechanism involved. The overarching aim is to find novel interventions to manipulate endocrine regulation of T cells and promote desirable immune outcomes.

Research collaborations

• Dr Sian Henson, Centre for Microvascular Research, Queen Marys, University of London, UK. T cell metabolism and immunosenescence.

• Prof Arne Akbar, Infection and Immunity, UCL, UK. T cell immunosenescence, cell signalling and human skin challenge model.

• Dr Anis Larbi, Singapore Immunology Network (SIgN), A*STAR Institute, Singapore. Telomere analysis, deep immunophenotyping, gene expression arrays and proteomics characterisation of immunosenescence.

• Prof Gary Frost and Dr Ed Chambers, Department of Investigative Medicine, Imperial College London, UK. Effects of nutrition, the microbiome and shift work on immune function.

• Prof Daniel Gomes, Universidade Federal do Espírito Santo, Brazil. Impact of immune ageing and neuroendocrine factors on Leishmania immunology.

• Dr Jos Bosch, Department of Clinical Psychology, University of Amsterdam. Netherlands. Experimental and epidemiological studies of psychoneuroimmunology.

Departmental duties

Academic lead for FACS facility

My teaching

Supervision

Postgraduate research supervision

My publications

Publications

Henson SM, Lanna A, Riddell N, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA, Akbar AN (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells, Journal of Clinical Investigation 124 (9) pp. 4004-4016 American Society for Clinical Investigation
T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-± and IFN-³ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway.
Zalli A, Bosch JA, Goodyear O, Riddell N, McGettrick HM, Moss P, Wallace GR (2015) Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly, Brain, Behavior, and Immunity 45 pp. 211-218
It is well-established that central nervous system activation affects peripheral blood mononuclear cell (PBMCs) function through the release of the catecholamines (Epi) and norepinephrine (NE), which act on ß2-adrenergic receptors (ß2AR). However, most studies have used non-specific stimulation of cells rather than antigen-specific responses. Likewise, few studies have parsed out the direct effects of ß2AR stimulation on T cells versus indirect effects via adrenergic stimulation of antigen presenting cells (APC). Here we report the effect of salmeterol (Sal), a selective ß2AR agonist, on IFN-³+ CD4 and IFN-³+ CD8 T cells following stimulation with Cytomegalovirus lysate (CMVL-strain AD169) or individual peptides spanning the entire region of the HCMV pp65 protein (pp65). Cells were also stimulated with Staphylococcal enterotoxin B. Additionally, we investigated the effect of Epi and Sal on cytotoxic cell killing of transfected target cells at the single cell level using the CD107a assay.

The results show that Sal reduced the percentage of IFN-³+ CD4 and IFN-³+ CD8 T cells both when applied directly to isolated T cells, and indirectly via treatment of APC. These inhibitory effects were mediated via a ß2 adrenergic-dependent pathway and were stronger for CD8 as compared to CD4 T cells. Similarly, the results show that Sal suppressed cytotoxicity of both CD8 T and NK cells in vitro following stimulation with Chinese hamster ovary cell line transfected with MICA*009 (T-CHO) and the human erythromyeloblastoid leukemic (K562) cell line. The inhibitory effect on cytotoxicity following stimulation with T-CHO was stronger in NK cells compared with CD8 T cells.

Thus, targeting the ß2AR on lymphocytes and on APC leads to inhibition of inflammatory cytokine production and target cell killing. Moreover, there is a hierarchy of responses, with CD8 T cells and NK cells inhibited more effectively than CD4 T cells.

Riddell N, Henson SM, Macaulay R, Nunn CJ, Akbar AN (2015) Blockade of PD-1 or p38 MAP Kinase signalling pathways enhances senescent human CD8+ T-cell proliferation by distinct pathways, European Journal of Immunology 45 (5) pp. 1441-1451 Wiley
Immune enhancement is desirable in situations where decreased immunity results in increased morbidity. We investigated whether blocking the surface inhibitory receptor PD-1 and/or p38 MAP kinase could enhance the proliferation of the effector memory CD8+ T-cell subset that re-expresses CD45RA (EMRA) and exhibits characteristics of senescence, which include decreased proliferation and telomerase activity but increased expression of the DNA damage response related protein ³H2AX. Blocking of both PD-1 and p38 MAPK signaling in these cells enhanced proliferation and the increase was additive when both pathways were inhibited simultaneously in both young and old human subjects. In contrast, telomerase activity in EMRA CD8+ T cells was only enhanced by blocking the p38 but not the PD-1 signaling pathway, further indicating that nonoverlapping signaling pathways were involved. Although blocking p38 MAPK inhibits TNF-± secretion in the EMRA population, this decrease was counteracted by the simultaneous inhibition of PD-1 signaling in these cells. Therefore, end-stage characteristics of EMRA CD8+ T cells are stringently controlled by distinct and reversible cell signaling events. In addition, the inhibition of PD-1 and p38 signaling pathways together may enable the enhancement of proliferation of EMRA CD8+ T cells without compromising their capacity for cytokine secretion.
Sansoni P, Vescovini R, Fagnoni FF, Akbar A, Arens R, Chiu Y-L, ?i
in-`ain L, Dechanet-Merville J, Derhovanessian E, Ferrando-Martinez S, Franceschi C, Frasca D, Fulöp T, Furman D, Gkrania-Klotsas E, Goodrum F, Grubeck-Loebenstein B, Hurme M, Kern F, Lilleri D, López-Botet M, Maier AB, Marandu T, Marchant A, Matheï C, Moss P, Muntasell A, Remmerswaal EBM, Riddell N, Rothe K, Sauce D, Shin E-C, Simanek AM, Smithey MJ, Söderberg-Nauclér C, Solana R, Thomas PG, van Lier R, Pawelec G, Nikolich-Zugich J
(2014) New advances in CMV and immunosenescence, Experimental Gerontology 55 pp. 54-62 Elsevier
Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on ?CMV & Immunosenescence?, held in Parma, Italy, 25?27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.
Riddell N, Griffiths SJ, Rivino L, King DCB, Teo GH, Henson SM, Cantisan S, Solana R, Kemeny DM, MacAry PA, Larbi A, Akbar AN (2015) Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults, Immunology 144 (4) pp. 549-560
Antigen-specific multifunctional T cells that secrete interferon-³, interleukin-2 and tumour necrosis factor-± simultaneously after activation are important for the control of many infections. It is unclear if these CD8+ T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+ CD27? T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8+ T cells that secrete interferon-³, interleukin-2 and tumour necrosis factor-± are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.
Riddell N, Burns VE, Wallace GR, Edwards KM, Drayson M, Redwine LS, Hong S, Bui JC, Fischer JC, Mills PJ, Bosch JA (2015) Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion, Brain, Behavior, and Immunity 49 pp. 49-53 Elsevier
Objectives

Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological ²-adrenergic (²AR) stimulation on peripheral PC numbers in humans.

Methods

In two studies, we investigated PC mobilization in response to an acute speech task (n = 26) and ²AR-agonist (isoproterenol) infusion (n = 20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the ²AR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs).

Results

Both psychological stress and ²AR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8+ T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a ²AR-agonist did not result in a significant change in circulating PCs.

Conclusion

PCs are rapidly mobilized by psychological stress via mechanisms independent of ²AR-stimulation, although the findings do not exclude ²AR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted.

Oakes T, Heather J, Best K, Byng-Maddick R, Husovsky C, Ismail M, Joshi K, Maxwell G, Noursadeghi M, Riddell N, Ruehl T, Turner C, Uddin I, Chain B (2017) Quantitative Characterization of the
t Cell Receptor Repertoire of Naïve
and Memory subsets Using an
Integrated experimental and
Computational Pipeline Which Is
Robust, economical, and Versatile,
Frontiers in Immunology 8 1267 Frontiers Media
The T cell receptor (TCR) repertoire can provide a personalized biomarker for infectious
and non-infectious diseases. We describe a protocol for amplifying, sequencing, and
analyzing TCRs which is robust, sensitive, and versatile. The key experimental step is
ligation of a single-stranded oligonucleotide to the 32 end of the TCR cDNA. This allows
amplification of all possible rearrangements using a single set of primers per locus. It
also introduces a unique molecular identifier to label each starting cDNA molecule. This
molecular identifier is used to correct for sequence errors and for effects of differential
PCR amplification efficiency, thus producing more accurate measures of the true TCR
frequency within the sample. This integrated experimental and computational pipeline
is applied to the analysis of human memory and naive subpopulations, and results in
consistent measures of diversity and inequality. After error correction, the distribution of
TCR sequence abundance in all subpopulations followed a power law over a wide range
of values. The power law exponent differed between naïve and memory populations, but
was consistent between individuals. The integrated experimental and analysis pipeline
we describe is appropriate to studies of T cell responses in a broad range of physiological
and pathological contexts.
Chambers Edward S., Byrne Claire S., Rugyendo Annette, Morrison Douglas J., Preston Tom, Tedford M. Catriona, Bell Jimmy D., Thomas E. Louise, Akbar Arne N., Riddell Natalie E., Sharma Rohini, Thursz Mark R., Manousou Pinelopi, Frost Gary (2018) The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease, Diabetes, Obesity and Metabolism Wiley
The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the
gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We
aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in
adults with non-alcoholic fatty liver disease (NAFLD). Eighteen adults were randomised to receive
20g/day of an inulin-propionate ester (IPE), designed to deliver propionate to the colon, or an
inulin-control for 42-days in a parallel design. The change in intrahepatocellular lipid (IHCL)
following the supplementation period was not different between groups (P=0.082), however IHCL
significantly increased within the inulin-control group (20.9±2.9 to 26.8±3.9%; P=0.012; n=9), which
was not observed within the IPE group (22.6±6.9 to 23.5±6.8%; P=0.635; n=9). The predominant
SCFA from colonic fermentation of inulin is acetate, which in a background of NAFLD and a
hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the
liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetatemediated
increase in IHCL.