ORCID Profile
0000-0001-6284-7061
Current Organisation
Monash University
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Publisher: Wiley
Date: 12-06-2012
DOI: 10.1038/ICB.2012.18
Abstract: Natural Regulatory T cells (Tregs) are defined by stable expression of the cell surface proteins CD4 and CD25, low surface expression of CD127 and expression of the transcription factor FOXP3. The contribution of Treg to the prevention of autoimmunity and the maintenance of immune homoestasis is the subject of ongoing interest, as alterations in Treg numbers and function are implicated in a wide range of diseases. The in vitro benchmark for determining Treg function is suppression of proliferation of unmatched effector T cells in a mixed lymphocyte reaction (MLR) over a 3-6-day time period. As an alternative to this assay, we show that a 7-h CD154 expression assay is rapid, simple and provides a reliable readout of suppressor function. Using multiple Treg-like cell types including natural (n)Treg, inducible (i)Treg and Treg cell lines, we show that suppression of CD154 expression is a surrogate for suppression of proliferation. We propose this as a suitable alternative to the MLR assay, as it is rapid and may be more amenable to high-throughput screening, analysing large cohorts of clinical s les or assaying transiently suppressive populations.
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: 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: Public Library of Science (PLoS)
Date: 26-12-2012
Publisher: Public Library of Science (PLoS)
Date: 13-05-2014
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.IJPARA.2017.05.004
Abstract: Global eradication of the human-infecting malaria parasite Plasmodium falciparum, the major cause of malaria mortality, is unlikely to be achieved without an effective vaccine. However, our limited understanding of how protective immune responses target malaria parasites in humans, and how to best elicit these immune responses through vaccination, has h ered vaccine development. The red blood cell invading stage of the parasite lifecycle (merozoite) displays antigens that are attractive vaccine candidates as they are accessible to antibodies and raise high antibody titres in naturally immune in iduals. The number of merozoite antigens that elicit an immune response, and their structural and functional ersity, has led to a large number of lead antigens being pursued as vaccine candidates. Despite being seemingly spoilt for choice in terms of vaccine candidates, there is still a lack of consensus on exactly how merozoite antibodies reduce parasitemia and malaria disease. In this review we describe the various immune mechanisms that can result from IgG opsonization of merozoites, and highlight recent developments that support a role for these functional antibodies in naturally acquired and vaccine-induced immunity.
Publisher: eLife Sciences Publications, Ltd
Date: 31-08-2021
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: Cold Spring Harbor Laboratory
Date: 13-04-2021
DOI: 10.1101/2021.04.07.21255038
Abstract: Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. 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-hemagglutinin (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 cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4 + T cells and have a erse 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. Antibody production upon vaccination requires antigen-specific cTfh cells whose formation is suppressed by pro-inflammatory cytokine signalling.
Publisher: Public Library of Science (PLoS)
Date: 09-09-2013
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/IAI.00145-16
Abstract: It is unclear whether naturally acquired immunity to Plasmodium falciparum results from the acquisition of antibodies to multiple, erse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or P. falciparum MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against erse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.
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: Wiley
Date: 05-06-2019
Abstract: CD4
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.CELLIMM.2012.04.002
Abstract: The peptidase inhibitor PI16 was shown previously by microarray analysis to be over-expressed by CD4-positive/CD25-positive Treg compared with CD4-positive/CD25-negative Th cells. Using a monoclonal antibody to the human PI16 protein, we found that PI16-positive Treg have a memory (CD45RO-positive) phenotype and express higher levels of FOXP3 than PI16-negative Treg. PI16-positive Treg are functional in suppressor assays in vitro with potency similar to PI16-negative Treg. Further phenotyping of the PI16-positive Treg revealed that the chemokine receptors CCR4 and CCR6 are expressed by more of the PI16-positive/CD45RO-positive Treg compared with PI16-negative/CD45RO-positive Treg or Th cells. PI16-positive Treg showed enhanced in vitro migration towards the inflammatory chemokines CCL17 and CCL20, suggesting they can migrate to sites of inflammation. We conclude that PI16 identifies a novel distinct subset of functional memory Treg which can migrate to sites of inflammation and regulate the pro-inflammatory response at those sites.
Publisher: Oxford University Press (OUP)
Date: 02-02-2015
Abstract: Increasing evidence suggests that antibodies against merozoite surface proteins (MSPs) play an important role in clinical immunity to malaria. Two unusual members of the MSP-3 family, merozoite surface protein duffy binding-like (MSPDBL)1 and MSPDBL2, have been shown to be extrinsically associated to MSP-1 on the parasite surface. In addition to a secreted polymorphic antigen associated with merozoite (SPAM) domain characteristic of MSP-3 family members, they also contain Duffy binding-like (DBL) domain and were found to bind to erythrocytes, suggesting that they play a role in parasite invasion. Antibody responses to these proteins were investigated in a treatment-reinfection study conducted in an endemic area of Papua New Guinea to determine their contribution to naturally acquired immunity. Antibodies to the SPAM domains of MSPDBL1 and MSPDBL2 as well as the DBL domain of MSPDBL1 were found to be associated with protection from Plasmodium falciparum clinical episodes. Moreover, affinity-purified anti-MSPDBL1 and MSPDBL2 were found to inhibit in vitro parasite growth and had strong merozoite opsonizing capacity, suggesting that protection targeting these antigens results from ≥2 distinct effector mechanisms. Together these results indicate that MSPDBL1 and MSPDBL2 are important targets of naturally acquired immunity and might constitute potential vaccine candidates.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.COI.2021.11.004
Abstract: T follicular helper (Tfh) cells are essential for the establishment, maintenance and output of the germinal centre (GC) response. The transient nature of this response, and its location within secondary lymphoid tissues have h ered our understanding of this critical cell type, particularly in humans. A counterpart of GC Tfh cells in peripheral blood has enabled recent discoveries in disease and vaccination settings, while direct s ling of lymph nodes provides exciting new avenues to study GC responses directly in vivo. Tfh differentiation is shaped by the cytokine milieu during inflammation, vaccination and with age, and disease-specific patterns are emerging. An improved understanding of how to support a Tfh response remains key to enhancing vaccine immunity across the lifespan.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.IMMUNI.2022.06.020
Abstract: Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4
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: 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: 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: MyJove Corporation
Date: 17-07-2014
DOI: 10.3791/51590
Publisher: Springer Science and Business Media LLC
Date: 15-06-2017
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.CELREP.2015.12.006
Abstract: Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-10-2022
DOI: 10.1126/SCIIMMUNOL.ABM8389
Abstract: Vaccines work largely by generating long-lived plasma cells (LLPCs), but knowledge of how such cells are recruited is sparse. Although it is clear that LLPCs preferentially originate in germinal centers (GCs) and relocate to survival niches in bone marrow where they can persist for decades, the issues of the timing of LLPC recruitment and the basis of their retention remain uncertain. Here, using a genetic timest ing system in mice, we show that persistent PCs accrue in bone marrow at an approximately constant rate of one cell per hour over a period spanning several weeks after a single immunization with a model antigen. Affinity-based selection was evident in persisting PCs, reflecting a relative and dynamic rather than absolute affinity threshold as evidenced by the changing pattern of V H gene somatic mutations conveying increased affinity for antigen. We conclude that the life span of persistent, antigen-specific PCs is in part intrinsic, preprogrammed, and varied and that their final number is related to the duration of the response in a predictable way. This implies that modulating vaccines to extend the duration of the GC reaction will enhance antibody-mediated protective immunity.
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.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Danika Hill.