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

University roles and responsibilities

  • Academic lead for FACS facility

    Research

    Research interests

    Research collaborations

    Supervision

    Postgraduate research supervision

    My teaching

    My publications

    Publications

    T Oakes, JM Heather, K Best, R Byng-Maddick, C Husovsky, M Ismail, K Joshi, G Maxwell, M Noursadeghi, Natalie Riddell, T Ruehl, CT Turner, I Uddin, B Chain (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, In: Frontiers in Immunology81267 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 3′ 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.

    Edward S. Chambers, Claire S. Byrne, Annette Rugyendo, Douglas J. Morrison, Tom Preston, M. Catriona Tedford, Jimmy D. Bell, E. Louise Thomas, Arne N. Akbar, Natalie E. Riddell, Rohini Sharma, Mark R. Thursz, Pinelopi Manousou, Gary Frost (2018)The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease, In: 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.

    SM Henson, A Lanna, N Riddell, O Franzese, R Macaulay, SJ Griffiths, DJ Puleston, AS Watson, AK Simon, SA Tooze, AN Akbar (2014)p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells, In: Journal of Clinical Investigation124(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-α and IFN-γ 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.

    Edward S. Chambers, Claire S. Byrne, Douglas J. Morrison, Kevin G. Murphy, Tom Preston, M. Catriona Tedford, Isabel Garcia-Perez, Sofia Fountana, Jose I. Serrano-Contreras, Elaine Holmes, Jordie F. Roberts, Catherine J. Reynolds, Rosemary J. Boyton, Daniel M. Altmann, Julie A.K. McDonald, Julian R. Marchesi, Arne N. Akbar, Natalie E. Riddell, Gareth A. Wallis, Gary Frost (2019)Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised crossover trial, In: Gut BMJ Publishing Group

    Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses. Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period. Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.

    P Sansoni, R Vescovini, FF Fagnoni, A Akbar, R Arens, Y-L Chiu, L Čičin-Šain, J Dechanet-Merville, E Derhovanessian, S Ferrando-Martinez, C Franceschi, D Frasca, T Fulöp, D Furman, E Gkrania-Klotsas, F Goodrum, B Grubeck-Loebenstein, M Hurme, F Kern, D Lilleri, M López-Botet, AB Maier, T Marandu, A Marchant, C Matheï, P Moss, A Muntasell, EBM Remmerswaal, N Riddell, K Rothe, D Sauce, E-C Shin, AM Simanek, MJ Smithey, C Söderberg-Nauclér, R Solana, PG Thomas, R van Lier, G Pawelec, J Nikolich-Zugich (2014)New advances in CMV and immunosenescence, In: Experimental Gerontology55pp. 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.

    Kimberley Smith, Shannon Gavey, Natalie Riddell, Panagiota Kontari, Christina Victor (2020)The association between loneliness, social isolation and inflammation: A systematic review and meta-analysis., In: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS PERGAMON-ELSEVIER SCIENCE LTD

    The review synthesised evidence examining the association between a.) loneliness with inflammation and b.) social isolation with inflammation in adults aged 16 or older from the general population. From an initial 7,400 articles we identified 14 papers that examined loneliness, and 16 that examined social isolation. Qualitative syntheses indicated mixed results, variable study quality, and methodological heterogeneity. Most studies provided associations for C-reactive protein (CRP), fibrinogen and Interleukin-6 (IL-6), and these results were synthesised using random-effects meta-analyses. There was no association between loneliness with CRP or fibrinogen, but there was a significant association between loneliness and IL-6 for most-adjusted (but not least-adjusted) analyses. There was also a significant least-adjusted association between social isolation with CRP and fibrinogen, which remained significant for fibrinogen in most-adjusted analyses. There was no association between social isolation with IL-6. Sensitivity analyses indicated that methodological heterogeneity impacted on results. Results indicate that social isolation and loneliness could be linked with systemic inflammation, but more robust methodology is needed to confirm these associations and unpack mechanisms.

    A Zalli, JA Bosch, O Goodyear, N Riddell, HM McGettrick, P Moss, GR Wallace (2015)Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly, In: Brain, Behavior, and Immunity45pp. 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-γ+ CD4 and IFN-γ+ 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-γ+ CD4 and IFN-γ+ 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.

    N Riddell, VE Burns, GR Wallace, KM Edwards, M Drayson, LS Redwine, S Hong, JC Bui, JC Fischer, PJ Mills, JA Bosch (2015)Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion, In: Brain, Behavior, and Immunity49pp. 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 β-adrenergic (βAR) 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 βAR-agonist (isoproterenol) infusion (n = 20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-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 βAR-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 βAR-agonist did not result in a significant change in circulating PCs. Conclusion PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted.

    N Riddell, SJ Griffiths, L Rivino, DCB King, GH Teo, SM Henson, S Cantisan, R Solana, DM Kemeny, PA MacAry, A Larbi, AN Akbar (2015)Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults, In: Immunology144(4)pp. 549-560

    Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α 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-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.

    N Riddell, SM Henson, R Macaulay, CJ Nunn, AN Akbar (2015)Blockade of PD-1 or p38 MAP Kinase signalling pathways enhances senescent human CD8+ T-cell proliferation by distinct pathways, In: European Journal of Immunology45(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 γH2AX. 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-α 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.

    Branca I. Pereira, Roel P. H. De Maeyer, Luciana P. Covre, Djamel Nehar-Belaid, Alessio Lanna, Sophie Ward, Radu Marches, Emma S. Chambers, Daniel C. O. Gomes, Natalie E. Riddell, Mala K. Maini, Vitor H. Teixeira, Samuel M. Janes, Derek W. Gilroy, Anis Larbi, Neil A. Mabbott, Duygu Ucar, George A. Kuchel, Sian M. Henson, Jessica Strid, Jun H. Lee, Jacques Banchereau, Arne N. Akbar (2020)Sestrins induce natural killer function in senescent-like CD8⁺ T cells, In: Nature Immunology21(6)pp. 684-694 Nature Research

    Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8⁺ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27⁻CD28⁻CD8⁺ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27⁻CD28⁻CD8⁺ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27⁻CD28⁻CD8⁺ T cells to acquire a broad-spectrum, innate-like killing activity.