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  1. Article: Thymus-derived hormonal and cellular control of cancer.

    Savino, Wilson / Lepletier, Ailin

    Frontiers in endocrinology

    2023  Volume 14, Page(s) 1168186

    Abstract: The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions ... ...

    Abstract The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions and orchestrate the immune responses against tumor cells, pathogens and self-antigens. The mechanisms supporting intrathymic T cell differentiation are pleiotropically regulated by thymic peptide hormones and cytokines produced by stromal cells in the thymic microenvironment and developing thymocytes. Interestingly, in the same way as T cells, thymic hormones (herein exemplified by thymosin, thymulin and thymopoietin), can circulate to impact immune cells and other cellular components in the periphery. Evidence on how thymic function influences tumor cell biology and response of patients with cancer to therapies remains unsatisfactory, although there has been some improvement in the knowledge provided by recent studies. Herein, we summarize research progression in the field of thymus-mediated immunoendocrine control of cancer, providing insights into how manipulation of the thymic microenvironment can influence treatment outcomes, including clinical responses and adverse effects of therapies. We review data obtained from clinical and preclinical cancer research to evidence the complexity of immunoendocrine interactions underpinning anti-tumor immunity.
    MeSH term(s) Humans ; Thymus Gland ; T-Lymphocytes ; Cytokines/metabolism ; Neoplasms/metabolism ; Peptides/metabolism ; Tumor Microenvironment
    Chemical Substances Cytokines ; Peptides
    Language English
    Publishing date 2023-07-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2023.1168186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: A high-resolution mass spectrometry based proteomic dataset of human regulatory T cells

    Weerakoon, Harshi / Miles, John J. / Lepletier, Ailin / Hill, Michelle M.

    Data in Brief. 2022 Feb., v. 40

    2022  

    Abstract: Regulatory T cells (Tregs) play a core role in maintaining immune tolerance, homeostasis, and host health. High-resolution analysis of the Treg proteome is required to identify enriched biological processes and pathways distinct to this important immune ... ...

    Abstract Regulatory T cells (Tregs) play a core role in maintaining immune tolerance, homeostasis, and host health. High-resolution analysis of the Treg proteome is required to identify enriched biological processes and pathways distinct to this important immune cell lineage. We present a comprehensive proteomic dataset of Tregs paired with conventional CD4⁺ (Conv CD4⁺) T cells in healthy individuals. Tregs and Conv CD4⁺ T cells were sorted to high purity using dual magnetic bead-based and flow cytometry-based methodologies. Proteins were trypsin-digested and analysed using label-free data-dependent acquisition mass spectrometry (DDA-MS) followed by label free quantitation (LFQ) proteomics analysis using MaxQuant software. Approximately 4,000 T cell proteins were identified with a 1% false discovery rate, of which approximately 2,800 proteins were consistently identified and quantified in all the samples. Finally, flow cytometry with a monoclonal antibody was used to validate the elevated abundance of the protein phosphatase CD148 in Tregs. This proteomic dataset serves as a reference point for future mechanistic and clinical T cell immunology and identifies receptors, processes, and pathways distinct to Tregs. Collectively, these data will lead to a better understanding of Treg immunophysiology and potentially reveal novel leads for therapeutics seeking Treg regulation.
    Keywords computer software ; data collection ; flow cytometry ; homeostasis ; humans ; immunosuppression ; magnetism ; mass spectrometry ; monoclonal antibodies ; proteome ; proteomics ; therapeutics
    Language English
    Dates of publication 2022-02
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 2786545-9
    ISSN 2352-3409
    ISSN 2352-3409
    DOI 10.1016/j.dib.2021.107687
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: A high-resolution mass spectrometry based proteomic dataset of human regulatory T cells.

    Weerakoon, Harshi / Miles, John J / Lepletier, Ailin / Hill, Michelle M

    Data in brief

    2021  Volume 40, Page(s) 107687

    Abstract: Regulatory T cells (Tregs) play a core role in maintaining immune tolerance, homeostasis, and host health. High-resolution analysis of the Treg proteome is required to identify enriched biological processes and pathways distinct to this important immune ... ...

    Abstract Regulatory T cells (Tregs) play a core role in maintaining immune tolerance, homeostasis, and host health. High-resolution analysis of the Treg proteome is required to identify enriched biological processes and pathways distinct to this important immune cell lineage. We present a comprehensive proteomic dataset of Tregs paired with conventional CD4
    Language English
    Publishing date 2021-12-06
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2786545-9
    ISSN 2352-3409 ; 2352-3409
    ISSN (online) 2352-3409
    ISSN 2352-3409
    DOI 10.1016/j.dib.2021.107687
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  4. Article ; Online: Streptococcus pyogenes vaccine candidates do not induce autoimmune responses in a rheumatic heart disease model.

    Reynolds, Simone / Rafeek, Rukshan Ahamed Mohamed / Hamlin, Adam / Lepletier, Ailin / Pandey, Manisha / Ketheesan, Natkunam / Good, Michael F

    NPJ vaccines

    2023  Volume 8, Issue 1, Page(s) 9

    Abstract: We have developed a candidate vaccine to protect against multiple strains of Streptococcus pyogenes infections. The candidate vaccine contains two synthetic peptides derived from S. pyogenes proteins: the M-protein epitope, p*17 and the IL-8 degrading S. ...

    Abstract We have developed a candidate vaccine to protect against multiple strains of Streptococcus pyogenes infections. The candidate vaccine contains two synthetic peptides derived from S. pyogenes proteins: the M-protein epitope, p*17 and the IL-8 degrading S. pyogenes Cell-Envelope Proteinase (SpyCEP) epitope, K4S2. In this study we utilise a rat autoimmune valvulitis model that displays both the cardiac and neurobehavioural pathology associated with post-streptococcal sequelae, to assess if the vaccine candidate antigens induce autoimmune complications and inflammatory pathology. Each antigen was conjugated to carrier protein diphtheria toxoid (DT) and independently assessed for potential to induce autoimmune pathology in female Lewis rats. Rats were administered three subcutaneous doses, and one intranasal dose over a four-week study with a two-week recovery period. A positive control group received recombinant S. pyogenes M5 (rM5) protein, and the negative control group received PBS. Rats that received rM5 developed significant cardiac and neurological pathologies. There was no evidence of these pathologies in the PBS control group, or the rats administered either P*17-DT or K4S2-DT. This study provides further preclinical evidence of the safety of the vaccine candidates p*17 and K4S2 and their appropriateness as candidates in human clinical trials.
    Language English
    Publishing date 2023-02-04
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-023-00604-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Integrative temporal multi-omics reveals uncoupling of transcriptome and proteome during human T cell activation.

    Weerakoon, Harshi / Mohamed, Ahmed / Wong, Yide / Chen, Jinjin / Senadheera, Bhagya / Haigh, Oscar / Watkins, Thomas S / Kazakoff, Stephen / Mukhopadhyay, Pamela / Mulvenna, Jason / Miles, John J / Hill, Michelle M / Lepletier, Ailin

    NPJ systems biology and applications

    2024  Volume 10, Issue 1, Page(s) 21

    Abstract: Engagement of the T cell receptor (TCR) triggers molecular reprogramming leading to the acquisition of specialized effector functions by CD4 helper and CD8 cytotoxic T cells. While transcription factors, chemokines, and cytokines are known drivers in ... ...

    Abstract Engagement of the T cell receptor (TCR) triggers molecular reprogramming leading to the acquisition of specialized effector functions by CD4 helper and CD8 cytotoxic T cells. While transcription factors, chemokines, and cytokines are known drivers in this process, the temporal proteomic and transcriptomic changes that regulate different stages of human primary T cell activation remain to be elucidated. Here, we report an integrative temporal proteomic and transcriptomic analysis of primary human CD4 and CD8 T cells following ex vivo stimulation with anti-CD3/CD28 beads, which revealed major transcriptome-proteome uncoupling. The early activation phase in both CD4 and CD8 T cells was associated with transient downregulation of the mRNA transcripts and protein of the central glucose transport GLUT1. In the proliferation phase, CD4 and CD8 T cells became transcriptionally more divergent while their proteome became more similar. In addition to the kinetics of proteome-transcriptome correlation, this study unveils selective transcriptional and translational metabolic reprogramming governing CD4 and CD8 T cell responses to TCR stimulation. This temporal transcriptome/proteome map of human T cell activation provides a reference map exploitable for future discovery of biomarkers and candidates targeting T cell responses.
    MeSH term(s) Humans ; Proteome/genetics ; CD3 Complex ; Transcriptome/genetics ; Multiomics ; Proteomics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism
    Chemical Substances Proteome ; CD3 Complex ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2024-02-28
    Publishing country England
    Document type Journal Article
    ISSN 2056-7189
    ISSN (online) 2056-7189
    DOI 10.1038/s41540-024-00346-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Disruption of IL-17-mediated immunosurveillance in the respiratory mucosa results in invasive

    Mills, Jamie-Lee / Lepletier, Ailin / Ozberk, Victoria / Dooley, Jessica / Kaden, Jacqualine / Calcutt, Ainslie / Huo, Yongbao / Hicks, Allan / Zaid, Ali / Good, Michael F / Pandey, Manisha

    Frontiers in immunology

    2024  Volume 15, Page(s) 1351777

    Abstract: Introduction: Streptococcus pyogenes: Methods: Here, we modeled single or repeated non-lethal intranasal (IN) : Results: Immunocompetent mice that received a single : Discussion: Our results demonstrated that IL-17 plays a critical role in ... ...

    Abstract Introduction: Streptococcus pyogenes
    Methods: Here, we modeled single or repeated non-lethal intranasal (IN)
    Results: Immunocompetent mice that received a single
    Discussion: Our results demonstrated that IL-17 plays a critical role in preventing invasive disease following
    MeSH term(s) Animals ; Mice ; Interleukin-17 ; Monitoring, Immunologic ; Respiratory Mucosa ; Streptococcal Infections ; Streptococcus pyogenes
    Chemical Substances Interleukin-17 ; Il17a protein, mouse
    Language English
    Publishing date 2024-03-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2024.1351777
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils.

    Ozberk, Victoria / Zaman, Mehfuz / Lepletier, Ailin / Eskandari, Sharareh / Kaden, Jacqualine / Mills, Jamie-Lee / Calcutt, Ainslie / Dooley, Jessica / Huo, Yongbao / Langshaw, Emma L / Ulett, Glen C / Batzloff, Michael R / Good, Michael F / Pandey, Manisha

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5963

    Abstract: Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; ... ...

    Abstract Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; diphtheria toxoid as a source of T cell help; and the immunostimulatory glycolipid, 3D(6-acyl) PHAD (PHAD), is able to induce long-lived humoral and cellular immunity. Mice genetically deficient in either mucosal antibodies or total antibodies are protected against S. pyogenes respiratory tract infection. Utilizing IL-17-deficient mice or depleting cellular subsets using antibodies, shows that the cellular responses encompassing, CD4
    MeSH term(s) Mice ; Animals ; Liposomes ; Streptococcus pyogenes ; Neutrophils ; Interleukin-17 ; Antigens, Bacterial ; Macrophages ; Administration, Intranasal ; Immunity, Mucosal ; Vaccines, Subunit ; Mice, Inbred BALB C
    Chemical Substances Liposomes ; Interleukin-17 ; Antigens, Bacterial ; Vaccines, Subunit
    Language English
    Publishing date 2023-09-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41410-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review.

    Lepletier, Ailin / Chidgey, Ann P / Savino, Wilson

    Gerontology

    2015  Volume 61, Issue 6, Page(s) 504–514

    Abstract: Thymic involution during aging is a major reason for the decreased production of naive T cells and reduced immunity. Alterations within the thymic microenvironment, characterized by the loss of function of thymic epithelial cells (TECs) and fibro- ... ...

    Abstract Thymic involution during aging is a major reason for the decreased production of naive T cells and reduced immunity. Alterations within the thymic microenvironment, characterized by the loss of function of thymic epithelial cells (TECs) and fibro-adipogenetic transformation, seem to underlie this process, mainly through declining communication between thymic stromal cells and developing thymocytes. Specifically, the signaling mediated by cytokines and hormones secreted by TECs declines during aging. Many therapies based on the manipulation of growth factors and hormones have succeeded in partially recovering the lymphoid compartment and promoting thymic function. However, considering that aging-induced thymic involution is multifactorial, the thymic reestablishment achieved with treatments that target isolated pathways is incomplete and transitory. Here, we discuss the development of three novel approaches for potentially sustained thymic recovery: the induction of sustained forkhead box N1 expression, the activation of endogenous thymic epithelial progenitor cells (TEPCs), and the generation of TEPCs from pluripotent stem cells. Combined approaches targeting both TECs and lymphoid cells will provide a potentially more effective strategy for sustained rejuvenation of the thymus.
    MeSH term(s) Aging/pathology ; Aging/physiology ; Cellular Microenvironment ; Epithelial Cells/physiology ; Forkhead Transcription Factors ; Humans ; Signal Transduction/physiology ; Thymus Gland/pathology
    Chemical Substances Forkhead Transcription Factors ; Whn protein
    Language English
    Publishing date 2015
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 193798-4
    ISSN 1423-0003 ; 0304-324X
    ISSN (online) 1423-0003
    ISSN 0304-324X
    DOI 10.1159/000375160
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms.

    Li, Xian-Yang / Das, Indrajit / Lepletier, Ailin / Addala, Venkateswar / Bald, Tobias / Stannard, Kimberley / Barkauskas, Deborah / Liu, Jing / Aguilera, Amelia Roman / Takeda, Kazuyoshi / Braun, Matthias / Nakamura, Kyohei / Jacquelin, Sebastien / Lane, Steven W / Teng, Michele Wl / Dougall, William C / Smyth, Mark J

    The Journal of clinical investigation

    2022  Volume 132, Issue 6

    Language English
    Publishing date 2022-03-15
    Publishing country United States
    Document type Journal Article ; Retraction of Publication
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI159825
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    Ua VI Zs.184: Show issues Location:
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  10. Article: Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity.

    Weerakoon, Harshi / Straube, Jasmin / Lineburg, Katie / Cooper, Leanne / Lane, Steven / Smith, Corey / Alabbas, Saleh / Begun, Jakob / Miles, John J / Hill, Michelle M / Lepletier, Ailin

    Clinical & translational immunology

    2021  Volume 10, Issue 9, Page(s) e1334

    Abstract: Objective: Adoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may ... ...

    Abstract Objective: Adoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies.
    Methods: Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity.
    Results: High-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative (CD49f
    Conclusion: Overall, our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.
    Language English
    Publishing date 2021-09-06
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2694482-0
    ISSN 2050-0068
    ISSN 2050-0068
    DOI 10.1002/cti2.1334
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