ORCID Profile
0000-0001-6047-1996
Current Organisations
University of Helsinki
,
Stanford University
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Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
DOI: 10.1038/S41590-022-01253-8
Abstract: The identification of CD4
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.XCRM.2022.100845
Abstract: Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.
Publisher: Wiley
Date: 2021
DOI: 10.1111/ACEL.13295
Publisher: Elsevier BV
Date: 2020
Publisher: Frontiers Media SA
Date: 15-05-2017
Publisher: Elsevier BV
Date: 02-2018
Publisher: Proceedings of the National Academy of Sciences
Date: 04-08-2014
Abstract: The balance between the retention of lymphocytes in lymph nodes and their exit is a key factor determining clonal burst size, differentiation, and the efficacy of pathogen clearance. Currently, it is understood that naïve and activated T cells regulate their migration using a similar system, that is, balancing CC chemokine receptor (CCR)7-mediated retention signals against Sphingosine-1 phosphate receptor-1 (S1PR1)-mediated exit signals. This study utilizes a mouse model to selectively deplete the cellular source of CCR7 ligands, the fibroblastic reticular cells, before or during viral infection. The study concludes that while retention of naïve lymphocytes does depend on the fibroblastic reticular cell, it may be a cell-autonomous response of activated T cells that allows them to determine in a cell-intrinsic manner the magnitude of clonal expansion.
Publisher: Wiley
Date: 18-08-2022
DOI: 10.1111/ACEL.13692
Abstract: Vaccines typically protect against (re)infections by generating pathogen‐neutralising antibodies. However, as we age, antibody‐secreting cell formation and vaccine‐induced antibody titres are reduced. Antibody‐secreting plasma cells differentiate from B cells either early post‐vaccination through the extrafollicular response or from the germinal centre (GC) reaction, which generates long‐lived antibody‐secreting cells. As the formation of both the extrafollicular antibody response and the GC requires the interaction of multiple cell types, the impaired antibody response in ageing could be caused by B cell intrinsic or extrinsic factors, or a combination of the two. Here, we show that B cells from older people do not have intrinsic defects in their proliferation and differentiation into antibody‐secreting cells in vitro compared to those from the younger donors. However, adoptive transfer of B cells from aged mice to young recipient mice showed that differentiation into extrafollicular plasma cells was favoured at the expense of B cells entering the GC during the early stages of GC formation. In contrast, by the peak of the GC response, GC B cells derived from the donor cells of aged mice had expanded to the same extent as those from the younger donors. This indicates that age‐related intrinsic B cell changes delay the GC response but are not responsible for the impaired antibody‐secreting response or smaller peak GC response in ageing. Collectively, this study shows that B cells from aged in iduals are not intrinsically defective in responding to stimulation and becoming antibody‐secreting cells, implicating B cell‐extrinsic factors as the primary cause of age‐associated impairment in the humoral immunity.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2016
DOI: 10.1038/NCOMMS10579
Abstract: T follicular regulatory (Tfr) cells are a subset of Foxp3 + regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the magnitude of the response. Despite an increased interest in the role of Tfr cells in humoral immunity, many fundamental aspects of their biology remain unknown, including whether they recognize self- or foreign antigen. Here we show that Tfr cells can be specific for the immunizing antigen, irrespective of whether it is a self- or foreign antigen. We show that, in addition to developing from thymic derived Treg cells, Tfr cells can also arise from Foxp3 − precursors in a PD-L1-dependent manner, if the adjuvant used is one that supports T-cell plasticity. These findings have important implications for Tfr cell biology and for improving vaccine efficacy by formulating vaccines that modify the Tfr:Tfh cell ratio.
Publisher: Wiley
Date: 02-04-2013
DOI: 10.1111/IMR.12049
Abstract: MicroRNAs are short, 19-24 nucleotide long, RNA molecules capable of regulating the longevity and, to a lesser extent, translation of messenger RNA (mRNA) species. The function of the microRNA network, and indeed, even that of in idual microRNA species, can have profoundly different roles in even a single cell type as the microRNA/mRNA composition evolves. As the role of microRNA within T cells has come under increasing scrutiny, several distinct checkpoints have been demonstrated to have a particular reliance on microRNA regulation. MicroRNAs are arguably most important in T cells during the earliest and last stages in T-cell biology. The first stages of early thymic differentiation have a crucial reliance on the microRNA network, while later stages and peripheral homeostasis are largely, although not completely, microRNA-independent. The most profound effects on T cells are in the activation of effector and regulatory functions of conventional and regulatory T cells, where microRNA deficiency results in a near-complete loss of function. In this review, we focus on integrating the research on in idual microRNA into a more global understanding of the function of the microRNA regulatory network in T cells.
Publisher: Elsevier
Date: 2010
Publisher: Frontiers Media SA
Date: 28-09-2018
Publisher: Frontiers Media SA
Date: 07-10-2014
Publisher: eLife Sciences Publications, Ltd
Date: 31-08-2021
Publisher: Elsevier
Date: 2016
DOI: 10.1016/BS.IRN.2016.08.009
Abstract: The departure from traditional lifestyles and the rising disease burden of mental disorders are increasing global health concerns. Changes in diet around the world mean that populations are now increasingly reliant on highly processed, poor quality foods, which have been linked to increased risk for mental disorder. Conversely, a nutrient-rich diet is understood to be protective of mental health, and researchers are now aiming to understand the biological underpinnings of this relationship. The gut microbiota has been proposed as a key mediator of this link, given its association with both diet and mental health. Importantly, several critical "windows of opportunity" for prevention and intervention have been identified, particularly early life and adolescence these are periods of rapid development and transition that provide a foundation for future health. Strategies that promote overall diet quality, high in fiber and nutrients, have been linked to increased microbial ersity and gut health. Improving diet quality and subsequent gut health may have benefits for in iduals' mental health, as well as the mental health of future generations. Here we discuss specific, targeted dietary and gut focused strategies for the prevention and treatment of mental disorder.
Publisher: eLife Sciences Publications, Ltd
Date: 02-11-2021
DOI: 10.7554/ELIFE.70554
Abstract: Antibody production following vaccination can provide protective immunity to subsequent infection by pathogens such as influenza viruses. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at-risk groups. Here, by studying the breadth of anti-haemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper (cTfh) cells was associated with high-titre antibody responses. Using Major Histocompatability Complex (MHC) class II tetramers, we demonstrate that HA-specific cTfh cells can derive from pre-existing memory CD4 + T cells and have a erse T cell receptor (TCR) repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together, this suggests that strategies that temporarily d en inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-02-2020
DOI: 10.1126/SCITRANSLMED.AAW9522
Abstract: The composition and function of the immune system in African children is linked to age, location, and anemia.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAUT.2018.11.006
Abstract: The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection. In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (T
Publisher: Springer Science and Business Media LLC
Date: 27-01-2010
DOI: 10.1007/S00281-009-0194-Z
Abstract: Follicular helper T cells have recently emerged as a separate CD4(+) T helper lineage specialised in provision of help to B cells. They develop independently from Th1, Th2 and Th17 cells and are critical for humoral immunity, including the generation of long-lived and high affinity plasma cells and memory cells crucial for long-term protection against infections. A stepwise differentiation programme has emerged in which T cell receptor (TCR) signalling strength, CD28-mediated costimulation, B cell-derived inducible costimulator ligand signals, induction of c-maf and actions of cytokines, including interleukin (IL)-6 and IL-21, lead to upregulation of the transcriptional repressor B cell lymphoma 6 (Bcl-6) that drives T follicular helper (Tfh) cell differentiation. Bcl-6 turns on a repression programme that targets Blimp-1, transcriptional regulators of other helper lineages and microRNAs. Their concerted actions modulate expression of chemokine receptors, surface molecules and cytokines critical for follicular homing and B cell helper functions. Here, we review the nature of Tfh cells providing help to B cells during the two phases of B cell activation that occur in the outer T zone and, for some B cells, in germinal centres (GC). Recent insights into the signalling events that drive terminal differentiation of Tfh cells critical for selecting somatically mutated GC B cells and the consequences of Tfh dysregulation for immunodeficiency and autoimmune pathology are discussed.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/NG.3531
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-08-2017
DOI: 10.1126/SCIIMMUNOL.AAN1487
Abstract: Circulating human T follicular regulatory (T fr ) cells are distinct from tissue T fr cells.
Publisher: Wiley
Date: 14-10-2018
DOI: 10.1111/IMCB.12199
Abstract: Antibody‐mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report erse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB /c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen‐specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B‐cell intrinsic defect in the regulation of class‐switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class‐switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-01-2023
Abstract: 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 soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, Sec22b -deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.
Publisher: Springer New York
Date: 2017
DOI: 10.1007/978-1-4939-7095-7_7
Abstract: Follicular regulatory T cells are a subset of Foxp3
Publisher: The American Association of Immunologists
Date: 27-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 27-10-2020
DOI: 10.1101/2020.10.27.357426
Abstract: The spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons.
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.IMMUNI.2009.07.002
Abstract: Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.IMMUNI.2014.12.009
Abstract: The mechanism by which regulatory T cells control the germinal center response is unknown. In this issue of Immunity, Wing et al. (2014) and Sage et al. (2014) demonstrate that CTLA-4 is a critical effector molecule used by regulatory T cells to control the germinal center.
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Society of Hematology
Date: 23-10-2014
DOI: 10.1182/BLOOD-2014-07-585976
Abstract: RTX treatment results in loss of human GC B cells. Human Tfh and Tfr cells do not require GC B cells for their maintenance.
Publisher: Wiley
Date: 06-05-2023
DOI: 10.1111/IMCB.12645
Abstract: Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus‐2 infection however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8 + T cells are important for killing virally infected cells, and vaccines that induce antigen‐specific CD8 + T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older in iduals. Here, we show that in aged mice, spike epitope–specific CD8 + T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV‐19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV‐19 elicits a good CD8 + T‐cell response in older bodies, but that typical age‐associated features are evident on these vaccine reactive T cells.
Publisher: Wiley
Date: 23-12-2014
DOI: 10.1038/ICB.2014.108
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
DOI: 10.1038/NI.3753
Publisher: Springer Science and Business Media LLC
Date: 28-10-2021
Publisher: Rockefeller University Press
Date: 07-06-2019
DOI: 10.1084/JEM.20190301
Abstract: The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood s les, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE–formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1186/S13059-019-1835-8
Abstract: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster , which we suspected of being involved in long-term memory. We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster , it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1016/J.COI.2020.03.007
Abstract: The germinal centre (GC) is a specialized cellular structure that forms in response to antigenic stimulation. It generates long-term humoral immunity through the production of memory B cells and long-lived antibody-secreting plasma cells. Conventional GCs form within secondary lymphoid organs, where networks of specialised stromal cells that form during embryogenesis act as the stage upon which the various GC immune cell players are brought together, nurtured and co-ordinated to generate a productive response. In non-lymphoid organs, ectopic GCs can form in response to persistent antigenic and inflammatory stimuli. Unlike secondary lymphoid tissues, non-lymphoid organs do not have a developmentally programmed stromal cell network capable of supporting the germinal centre reaction therefore, the local tissue stroma must be remodelled by inflammatory stimuli in order to host a GC reaction. These ectopic GCs produce memory B cells and plasma cells that form a critical component of the humoral immune response.
Publisher: Elsevier BV
Date: 10-2016
Abstract: Immune responses demonstrate a high level of intra-species variation, compensating for the specialization capacity of pathogens. The recent advent of in-depth immune phenotyping projects in large-scale cohorts has allowed a first look into the factors that shape the inter-in idual ersity of the human immune system. Genetic approaches have identified genetic ersity as drivers of 20-40% of the variation between the immune systems of in iduals. The remaining 60-80% is shaped by intrinsic factors, with age being the predominant factor, as well as by environmental influences, where cohabitation and chronic viral infections were identified as key mediators. We review and integrate the recent in-depth large-scale studies on human immune ersity and its potential impact on health. VIDEO ABSTRACT.
Publisher: eLife Sciences Publications, Ltd
Date: 24-03-2020
DOI: 10.7554/ELIFE.52473
Abstract: Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older in iduals.
Publisher: eLife Sciences Publications, Ltd
Date: 27-10-2014
DOI: 10.7554/ELIFE.03180
Abstract: The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4+ T cells after priming. We show that continued CD28 expression is important for effector CD4+ T cells following infection maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.
Publisher: Frontiers Media SA
Date: 09-08-2022
DOI: 10.3389/FIMMU.2022.940705
Abstract: In the last century, we have seen a dramatic rise in the number of older persons globally, a trend known as the grey (or silver) tsunami. People live markedly longer than their predecessors worldwide, due to remarkable changes in their lifestyle and in progresses made by modern medicine. However, the older we become, the more susceptible we are to a series of age-related pathologies, including infections, cancers, autoimmune diseases, and multi-morbidities. Therefore, a key challenge for our modern societies is how to cope with this fragile portion of the population, so that everybody could have the opportunity to live a long and healthy life. From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs (SLOs) of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies. In this review, we will analyze the current state of understandings about the role of Tregs in acute and chronic infections as well as in vaccination response in both humans and mice. Lastly, we provide an overview of current strategies for Treg modulation with potential future applications to improve the effectiveness of vaccines in older in iduals.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.COI.2017.03.001
Abstract: Secondary lymphoid organs are organized into distinct zones, governed by different types of mesenchymal stromal cells. These stromal cell subsets are critical for the generation of protective humoral immunity because they direct the migration of, and interaction between, multiple immune cell types to form the germinal centre. The germinal centre response generates long-lived antibody-secreting plasma cells and memory B cells which can provide long-term protection against re-infection. Stromal cell subsets mediate this response through control of immune cell trafficking, activation, localization and antigen access within the secondary lymphoid organ. Further, distinct populations of stromal cells underpin the delicate spatial organization of immune cells within the germinal centre. Because of this, the interactions between immune cells and stromal cells in secondary lymphoid organs are fundamental to the germinal centre response. Herein we review how this unique relationship leads to effective germinal centre responses.
Publisher: Elsevier BV
Date: 11-2022
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-05-2022
DOI: 10.1126/SCIIMMUNOL.ABK0018
Abstract: The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule–1 (MAdCAM-1)–expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1 + stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1 + stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2010
DOI: 10.1007/S10875-010-9378-5
Abstract: MicroRNA are emerging as key regulators of the development and function of adaptive immunity. These 19-24 nucleotide regulatory RNA molecules have essential roles in multiple faucets of adaptive immunity, from regulating the development of the key cellular players to the activation and function in immune responses. MicroRNA are involved in T cell and B cell differentiation in the thymus and bone marrow, and subsequent peripheral homeostasis. The contribution of specific microRNA to the adaptive immune response becomes even more apparent during the effector phases: class switching and germinal centre formation in B cells, differentiation into functional lineages in T cells, and activation of antigen-presentation cells through pattern-recognition pathways. With the capacity of microRNA to alter the survival and death of T and B cells, control over microRNA expression is essential to prevent adaptive immune cells from unregulated proliferation. MicroRNA can act both as 'oncomirs' and tumour suppressors, and thus dysregulation of microRNA in lymphocytes can cause malignancies. In this review, we will describe the role of microRNA in generating a productive adaptive response, and the consequences if microRNA-mediated repression of lymphocytes is perturbed.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1007/S00018-017-2456-6
Abstract: MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the in idual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2019
DOI: 10.1038/S41467-019-09434-0
Abstract: Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.
Publisher: Cold Spring Harbor Laboratory
Date: 17-05-2019
DOI: 10.1101/641589
Abstract: The germinal centre (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunisation. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3 + Treg cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC, and the mechanism/s through which they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localisation to the GC. Here we show that the lack of CXCR5 on Foxp3 + regulatory T cells resulted in a reduced frequency, but not an absence of, GC-localised Tfr cells. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.
Publisher: Springer Science and Business Media LLC
Date: 05-2023
DOI: 10.1038/S41591-023-02343-2
Abstract: Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated in iduals with severe obesity (BMI 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 in iduals with severe obesity compared to 41 control in iduals with normal BMI (BMI 18.5–24.9 kg/m 2 ). We found that 55% of in iduals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of in iduals with normal BMI ( P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for in iduals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of in iduals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in in iduals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2021
DOI: 10.1038/S41586-021-03739-1
Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in in iduals above eighty years of age 1 . Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine 2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older in iduals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2011
DOI: 10.1038/NI.2193
Publisher: Cold Spring Harbor Laboratory
Date: 17-05-2021
DOI: 10.1101/2021.05.16.444192
Abstract: The neuropeptide Substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G q and G s proteins. Neurokinin A also activates NK1R, but leads to selective G q signaling. How two stimuli yield distinct G-protein signaling at the same G-protein-coupled-receptor remains unclear. We determined cryo-EM structures of active NK1R bound to SP or the G q -biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G s signaling but not G q signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility deep in the NK1R pocket. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G-protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.
Publisher: Wiley
Date: 23-02-2015
Publisher: Wiley
Date: 2014
DOI: 10.1038/ICB.2013.86
Publisher: Cold Spring Harbor Laboratory
Date: 25-04-2023
DOI: 10.1101/2023.04.24.538044
Abstract: Affinity maturation, the progressive increase in serum antibody affinity after vaccination, is an essential process that contributes to an effective humoral response against vaccines and infections. Germinal centres (GCs) are key for affinity maturation, as they are where B cells undergo somatic hypermutation of their immunoglobulin genes in the dark zone, before going through positive selection in the light zone via interactions with T follicular helper cells and follicular dendritic cells. In aged mice, affinity maturation has been shown to be impaired, but whether B cell-intrinsic factors contribute to this defect remains unclear. In this study, we show that B cells from aged B cell receptor transgenic mice are able to become GC B cells, which are capable of receiving positive selection signals to a similar extent as B cells from young adult mice. Consistent with this, ageing also does not impact the ability of B cells to undergo somatic hypermutation and acquire affinity-enhancing mutations. Together, this shows that there are no B cell-intrinsic defects in affinity maturation with age when the B cell receptor repertoire is constant.
Publisher: Research Square Platform LLC
Date: 15-06-2022
DOI: 10.21203/RS.3.RS-1733421/V1
Abstract: Vaccination generates long-lived antibody-mediated immunity against (re-)infection. This humoral immunity is derived from memory B cells and long-lived antibody-secreting plasma cells via the germinal centre (GC) response. The magnitude and quality of the GC response declines with age, resulting in poor vaccine-induced immunity in older in iduals, but the causal factor/s of this age-related decline are unknown. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. We identified that the spatial organisation of the GC is altered in ageing, with CXCR4-mediated mislocalisation of T follicular helper (Tfh) cells in the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. By modulating the positioning of Tfh cells in vivo, we found that Tfh cell polarisation is critical for the quality of the antibody response, and, surprisingly, for the expansion of the FDC network upon immunisation. The smaller GC responses and defective FDC expansion in ageing were corrected by provision of Tfh cells that co-localise with FDCs via CXCR5:CXCL13-mediated interaction. This demonstrates that the age-dependent defects in the GC response are reversible and shows that Tfh cells have a dual role in B cell help and facilitating stromal cell responses to vaccines.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Springer Science and Business Media LLC
Date: 22-05-2023
DOI: 10.1038/S41590-023-01519-9
Abstract: The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older in iduals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (T FH ) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that T FH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of T FH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that T FH cells support stromal cell responses to vaccines.
Publisher: LIDSEN Publishing Inc
Date: 02-06-2019
Publisher: Rockefeller University Press
Date: 05-02-2019
DOI: 10.1084/JEM.20181216
Abstract: Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2011
DOI: 10.1038/NM.2425
Publisher: Frontiers Media SA
Date: 22-01-2019
Publisher: Wiley
Date: 17-07-2017
DOI: 10.1111/IMM.12778
Publisher: Frontiers Media SA
Date: 23-01-2019
Publisher: Springer Science and Business Media LLC
Date: 19-08-2021
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41467-021-23220-X
Abstract: Follicular helper T (T FH ) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate T FH function has been found in in iduals with ineffective responses to vaccines, but the mechanism underlying T FH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human T FH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs T FH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of T FH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.
Publisher: Frontiers Media SA
Date: 25-10-2018
Publisher: Rockefeller University Press
Date: 18-08-2020
DOI: 10.1084/JEM.20201105
Abstract: T cell regulation of antibody-mediated immunity is critical for health. In this issue of JEM, Li et al. (0.1084/jem.20191537) identify the Cbl family of E3 ubiquitin ligases as B cell–intrinsic gatekeepers of T cell–dependent humoral immunity.
Publisher: Cold Spring Harbor Laboratory
Date: 07-05-2020
DOI: 10.1101/2020.05.07.082255
Abstract: The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center response, which generates long-lived antibody-secreting cells that provide protection against (re)infection. Despite intensive investigation into the effect of age on the lymphoid compartment, the primary cellular defect that causes impaired germinal centers in aging has not been identified. Herein we demonstrate that aging reduces the capacity of germinal center-associated stromal cells to respond to vaccination. Heterochronic parabiosis and mathematical modeling demonstrate that a poor stromal cell response limits the size of the germinal center. This study reveals that age-associated defects in stromal cells are a significant barrier to efficacious vaccine responses in older in iduals.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
DOI: 10.1038/S41467-019-10430-7
Abstract: Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer’s patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older in iduals by providing appropriate stimuli.
Publisher: F1000 Research Ltd
Date: 20-01-2016
DOI: 10.12688/F1000RESEARCH.7388.1
Abstract: The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection this in turn depends on a robust germinal centre (GC) response that culminates in the production of long-lived antibody-secreting plasma cells. The size and quality of the GC response are directed by a specialised subset of CD4 + T cells: T follicular helper (Tfh) cells. Tfh cells provide growth and differentiation signals to GC B cells and mediate positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as plasma cells and memory B cells. Because of their central role in the production of long-lasting humoral immunity, Tfh cells represent an interesting target for rational vaccine design.
Publisher: Frontiers Media SA
Date: 31-05-2018
Publisher: Frontiers Media SA
Date: 18-05-2017
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1038/NI.3856
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 2022
Publisher: eLife Sciences Publications, Ltd
Date: 28-02-2020
Publisher: Wiley
Date: 12-11-2013
DOI: 10.1038/ICB.2013.77
Abstract: Normal ageing is accompanied by a decline in the function of the immune system that causes an increased susceptibility to infections and an impaired response to vaccination in older in iduals. This results in an increased disease burden in the aged population, even with good immunisation programmes in place. The decreased response to vaccination is partly due to the diminution of the germinal centre response with age, caused by impaired T-cell help to B cells. Within the germinal centre, T-cell help is provided by a specialised subset of CD4(+) T cells T follicular helper (Tfh) cells. Tfh cells provide survival and selection signals to germinal centre B cells, allowing them to egress from the germinal centre and become long-live plasma cells or memory B cells, and provide life-long protection against subsequent infection. This review will discuss the cellular and molecular changes in both Tfh cells and germinal centre B cells that occur with advancing age, which result in a smaller germinal centre response and a less effective response to immunisation.
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.09.22276196
Abstract: Obesity is associated with an increased risk of severe Covid-19. However, the effectiveness of SARS-CoV-2 vaccines in people with obesity is unknown. Here we studied the relationship between body mass index (BMI), hospitalization and mortality due to Covid-19 amongst 3.5 million people in Scotland. Vaccinated people with severe obesity (BMI kg/m 2 ) were significantly more likely to experience hospitalization or death from Covid-19. Excess risk increased with time since vaccination. To investigate the underlying mechanisms, we conducted a prospective longitudinal study of the immune response in a clinical cohort of vaccinated people with severe obesity. Compared with normal weight people, six months after their second vaccine dose, significantly more people with severe obesity had unquantifiable titres of neutralizing antibody against authentic SARS-CoV-2 virus, reduced frequencies of antigen-experienced SARS-CoV-2 Spike-binding B cells, and a dissociation between anti-Spike antibody levels and neutralizing capacity. Neutralizing capacity was restored by a third dose of vaccine, but again declined more rapidly in people with severe obesity. We demonstrate that waning of SARS-CoV-2 vaccine-induced humoral immunity is accelerated in people with severe obesity and associated with increased hospitalization and mortality from breakthrough infections. Given the prevalence of obesity, our findings have significant implications for global public health.
Publisher: Springer International Publishing
Date: 2020
Publisher: Wiley
Date: 13-04-2012
Publisher: Wiley
Date: 13-05-2020
DOI: 10.1111/IMCB.12341
Publisher: Wiley
Date: 19-08-2010
Publisher: Springer Science and Business Media LLC
Date: 07-09-2016
Publisher: Elsevier BV
Date: 03-2020
Start Date: 2015
End Date: 2020
Funder: European Research Council
View Funded ActivityStart Date: 2022
End Date: 2027
Funder: UK Research and Innovation
View Funded ActivityStart Date: 2021
End Date: 2023
Funder: Medical Research Council
View Funded ActivityStart Date: 2020
End Date: 2022
Funder: Dunhill Medical Trust
View Funded ActivityStart Date: 2021
End Date: 2024
Funder: Biotechnology and Biological Sciences Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: Biotechnology and Biological Sciences Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Biotechnology and Biological Sciences Research Council
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Biotechnology and Biological Sciences Research Council
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: European Commission
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Biotechnology and Biological Sciences Research Council
View Funded Activity