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Article ; Online: Unlocking the Role of Exercise on CD4+ T Cell Plasticity.

Goldsmith, Chloé D / Donovan, Thomasina / Vlahovich, Nicole / Pyne, David B

2021 Volume 12, Page(s) 729366

Abstract: A hallmark of T cell ageing is a loss of effector plasticity. Exercise delays T cell ageing ... yet the mechanisms driving the effects of exercise on T cell biology are not well elucidated. T cell plasticity is ... In this perspective we propose a role for exercise in CD4+ T cell plasticity, exploring links between exercise ...

Abstract	A hallmark of T cell ageing is a loss of effector plasticity. Exercise delays T cell ageing, yet the mechanisms driving the effects of exercise on T cell biology are not well elucidated. T cell plasticity is closely linked with metabolism, and consequently sensitive to metabolic changes induced by exercise. Mitochondrial function is essential for providing the intermediate metabolites necessary to generate and modify epigenetic marks in the nucleus, thus metabolic activity and epigenetic mechanisms are intertwined. In this perspective we propose a role for exercise in CD4+ T cell plasticity, exploring links between exercise, metabolism and epigenetic reprogramming.
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Plasticity ; Cellular Senescence/genetics ; Cellular Senescence/immunology ; Chromatin Assembly and Disassembly ; Energy Metabolism ; Epigenesis, Genetic ; Exercise/genetics ; Exercise/immunology ; Humans ; Immunosenescence/genetics ; Immunosenescence/immunology ; Mitochondria/genetics ; Mitochondria/immunology ; Mitochondria/metabolism ; Phenotype
Language	English
Publishing date	2021-10-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.729366
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Article ; Online: Enhanced T cell effector activity by targeting the Mediator kinase module.

Science (New York, N.Y.)

2022 Volume 378, Issue 6620, Page(s) eabn5647

Abstract: T cells are the major arm of the immune system responsible for controlling and regressing cancers ... To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric ... antigen receptor (CAR) T cells. Top hits were ...

Abstract	T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were
MeSH term(s)	Humans ; Cyclin-Dependent Kinase 8/metabolism ; Cyclin-Dependent Kinases/metabolism ; Mediator Complex/genetics ; T-Lymphocytes/immunology ; Transcription Factors/genetics ; Receptors, Chimeric Antigen ; Genome-Wide Association Study ; Cyclin C/genetics ; Genetic Testing ; Immunotherapy, Adoptive ; Neoplasms/immunology ; Neoplasms/therapy
Chemical Substances	Cyclin-Dependent Kinase 8 (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Mediator Complex ; Transcription Factors ; Receptors, Chimeric Antigen ; MED12 protein, human ; CCNC protein, human ; Cyclin C
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abn5647
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Article ; Online: ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas.

Jiang, Baishan / Weinstock, David M / Donovan, Katherine A / Sun, Hong-Wei / Wolfe, Ashley / Amaka, Sam / Donaldson, Nicholas L / Wu, Gongwei / Jiang, Yuan / Wilcox, Ryan A / Fischer, Eric S / Gray, Nathanael S / Wu, Wenchao

Cell chemical biology

2023 Volume 30, Issue 4, Page(s) 383–393.e6

Abstract: Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling ... and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no ... inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T ...

Abstract	Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
MeSH term(s)	Humans ; Signal Transduction ; Receptors, Antigen, T-Cell/metabolism ; Drug Resistance, Neoplasm ; T-Lymphocytes ; Lymphoma, T-Cell/drug therapy
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.03.007
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Article: Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review.

Donovan, Thomasina / Bain, Amanda L / Tu, Wenjuan / Pyne, David B / Rao, Sudha

Frontiers in physiology

2021 Volume 12, Page(s) 668327

Abstract: The impaired effector function of exhausted and senescent T cells is implicated in cancer ... the interactions between exercise and exhausted and senescent T cells remain unclear. We therefore performed ...

Abstract	The impaired effector function of exhausted and senescent T cells is implicated in cancer progression and inadequate vaccine responses. Exercise has been shown to improve cancer therapy and vaccine efficacy, most likely by improving immune function. However, given inconsistent terminology and definitions, the interactions between exercise and exhausted and senescent T cells remain unclear. We therefore performed a systematic review to investigate the effect of exercise on senescent and exhausted CD8
Language	English
Publishing date	2021-08-20
Publishing country	Switzerland
Document type	Systematic Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.668327
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Article ; Online: Immunophenotyping of canine T cell activation and proliferation by combined protein and RNA flow cytometry.

Zhu, Xu / Rogers, Kara / Bono, Christine / Wang, Zhenyu / Donovan, Carol / Ji, Changhua

Veterinary immunology and immunopathology

2024 Volume 270, Page(s) 110739

Abstract: ... RNA-based flow cytometry to characterize canine T cell activation and proliferation within individual ... ionomycin. Robust T cell activation (CD25+ and/or CD69+) and proliferation (Ki67+) were detected. Both CD69 ... and CD25 appear to be robust and sensitive T cell activation markers with early induction and low ...

Abstract	The limited availability of canine-reactive monoclonal antibodies restricts the analyses of immune cell subsets and their functions by flow cytometry. The PrimeFlow™ RNA Assay may serve as a potential solution to close this gap. Here we report a blood immunophenotyping method utilizing combined protein- and RNA-based flow cytometry to characterize canine T cell activation and proliferation within individual cells. In this assay, CD69 expression was detected by an RNA probe and CD25 and Ki67 were detected by antibodies. Canine peripheral blood mononuclear cells (PBMCs) were stimulated with three agents with different modes of action, anti-CD3/CD28 antibodies, phytohemagglutinin, or phorbol myristate acetate /ionomycin. Robust T cell activation (CD25+ and/or CD69+) and proliferation (Ki67+) were detected. Both CD69 and CD25 appear to be robust and sensitive T cell activation markers with early induction and low background expression. Upon stimulation, T cell proliferation occurred later than T cell activation and was associated with CD25 expression. This canine T cell activation and proliferation immunophenotyping method was evaluated in 5 independent experiments using PBMCs from 10 different beagle dogs with satisfactory assay performance. This method can greatly facilitate the evaluation of immune disease pathogenesis and immunotoxicity risk assessment in nonclinical drug development in canine.
MeSH term(s)	Dogs ; Animals ; Antigens, CD ; Leukocytes, Mononuclear ; RNA/metabolism ; Ki-67 Antigen ; Flow Cytometry/veterinary ; Flow Cytometry/methods ; Immunophenotyping/veterinary ; T-Lymphocytes ; Cell Proliferation ; Lymphocyte Activation
Chemical Substances	Antigens, CD ; RNA (63231-63-0) ; Ki-67 Antigen
Language	English
Publishing date	2024-02-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	754160-0
ISSN	1873-2534 ; 0165-2427
ISSN (online)	1873-2534
ISSN	0165-2427
DOI	10.1016/j.vetimm.2024.110739
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Zs.A 2177: Show issues

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Article: Identification of a small molecule for enhancing lentiviral transduction of T cells.

Malach, Paulina / Kay, Charlotte / Tinworth, Chris / Patel, Florence / Joosse, Bryan / Wade, Jennifer / Rosa do Carmo, Marlene / Donovan, Brian / Brugman, Martijn / Montiel-Equihua, Claudia / Francis, Natalie

Molecular therapy. Methods & clinical development

2023 Volume 31, Page(s) 101113

Abstract: ... In this study, we aimed to identify molecules capable of enhancing lentiviral transduction of T cells ... testing with two therapeutic lentiviral vectors used to manufacture GSK's clinical T cell therapy products ... of the lead compound. Finally, we demonstrate the ability of the lead transduction enhancer to produce a comparable T ...

Abstract	Genetic modification of cells using viral vectors has shown huge therapeutic benefit in multiple diseases. However, inefficient transduction contributes to the high cost of these therapies. Several transduction-enhancing small molecules have previously been identified; however, some may be toxic to the cells or patient, otherwise alter cellular characteristics, or further increase manufacturing complexity. In this study, we aimed to identify molecules capable of enhancing lentiviral transduction of T cells from available small-molecule libraries. We conducted a high-throughput flow-cytometry-based screen of 27,892 compounds, which subsequently was narrowed down to six transduction-enhancing small molecules for further testing with two therapeutic lentiviral vectors used to manufacture GSK's clinical T cell therapy products. We demonstrate enhanced transduction without a negative impact on other product attributes. Furthermore, we present results of transcriptomic analysis, suggesting alteration of ribosome biogenesis, resulting in reduced interferon response, as a potential mechanism of action for the transduction-enhancing activity of the lead compound. Finally, we demonstrate the ability of the lead transduction enhancer to produce a comparable T cell product using a 3-fold reduction in vector volume in our clinical manufacturing process, resulting in a predicted 15% reduction in the overall cost of goods.
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.101113
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Zs.A 7107: Show issues

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Article ; Online: FANCA c.3624C>T (p.Ser1208=) is a hypomorphic splice variant associated with delayed onset of Fanconi anemia.

Ramanagoudr-Bhojappa, Ramanagouda / Tryon, Rebecca / Lach, Francis P / Donovan, Frank X / Maxwell, Rochelle / Rosenberg, Allana / MacMillan, Margaret L / Wagner, John E / Auerbach, Arleen D / Smogorzewska, Agata / Chandrasekharappa, Settara C

Blood advances

2024 Volume 8, Issue 4, Page(s) 899–908

Abstract: ... FANCA variant and 1 FANCA exon 36 variant, c.3624C>T. These individuals had delayed onset ... Although predicted to encode a synonymous change (p.Ser1208=), the c.3624C>T variant causes a splicing error ... cross-linking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T ...

Abstract	Abstract: Fanconi anemia (FA) is a hereditary, DNA repair deficiency disorder caused by pathogenic variants in any 1 of 22 known genes (FANCA-FANCW). Variants in FANCA account for nearly two-thirds of all patients with FA. Clinical presentation of FA can be heterogeneous and include congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. Here, we describe a relatively mild disease manifestation among 6 individuals diagnosed with FA, each compound heterozygous for 1 established pathogenic FANCA variant and 1 FANCA exon 36 variant, c.3624C>T. These individuals had delayed onset of hematological abnormalities, increased survival, reduced incidence of cancer, and improved fertility. Although predicted to encode a synonymous change (p.Ser1208=), the c.3624C>T variant causes a splicing error resulting in a FANCA transcript missing the last 4 base pairs of exon 36. Deep sequencing and quantitative reverse transcription polymerase chain reaction analysis revealed that 6% to 10% of the FANCA transcripts included the canonical splice product, which generated wild-type FANCA protein. Consistently, functional analysis of cell lines from the studied individuals revealed presence of residual FANCD2 ubiquitination and FANCD2 foci formation, better cell survival, and decreased late S/G2 accumulation in response to DNA interstrand cross-linking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T variant is a hypomorphic allele, which contributes to delayed manifestation of FA disease phenotypes in individuals with at least 1 c.3624C>T allele.
MeSH term(s)	Humans ; Fanconi Anemia Complementation Group A Protein/genetics ; Fanconi Anemia/genetics ; Cell Line ; Genotype ; Neoplasms
Chemical Substances	Fanconi Anemia Complementation Group A Protein ; FANCA protein, human
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011888
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Zs.A 7153: Show issues

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Article ; Online: Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells.

Halliwell, Emma / Vitali, Alice / Muller, Henrike / Alonso-Ferrero, Maria / Barisa, Marta / Gavriil, Artemis / Piapi, Alice / Leboreiro-Babe, Clara / Gileadi, Talia / Yeung, Jenny / Pataillot-Meakin, Thomas / Fisher, Jonathan / Tucker, Lizzie / Donovan, Laura / Chesler, Lou / Chester, Kerry / Anderson, John

Cytotherapy

2022 Volume 25, Issue 1, Page(s) 46–58

Abstract: Background aims: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces ... of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood ... target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened ...

Abstract	Background aims: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces many technological hurdles, including selection of optimal target antigens. Promising pre-clinical and clinical data of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood cancer neuroblastoma. Anaplastic lymphoma kinase (ALK) is expressed in a majority of neuroblastomas at low antigen density but is largely absent from healthy tissues. Methods: To explore an alternate target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened a single-chain variable fragment library targeting ALK extracellular domain to make a panel of new anti-ALK CAR T-cell constructs. Results: A lead novel CAR T-cell construct was capable of specific cytotoxicity against neuroblastoma cells expressing low levels of ALK, but with only weak cytokine and proliferative T-cell responses. To explore strategies for amplifying ALK CAR T cells, the authors generated a co-CAR approach in which T cells received signal 1 from a first-generation ALK construct and signal 2 from anti-B7H3 or GD2 chimeric co-stimulatory receptors. The co-CAR approach successfully demonstrated the ability to avoid targeting single-antigen-positive targets as a strategy for mitigating on-target off-tumor toxicity. Conclusions: These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/genetics ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Gangliosides ; Neuroblastoma/genetics ; Neuroblastoma/therapy ; T-Lymphocytes ; Immunotherapy, Adoptive ; Antibodies ; Logic
Chemical Substances	Receptors, Antigen, T-Cell ; Gangliosides ; Antibodies
Language	English
Publishing date	2022-11-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2022.10.007
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Zs.A 5601: Show issues

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Article: Analysing the Combined Effects of Radiotherapy and Chemokine Receptor 5 Antagonism: Complementary Approaches to Promote T Cell Function and Migration in Oesophageal Adenocarcinoma.

Davern, Maria / O' Donovan, Cillian / Donlon, Noel E / Mylod, Eimear / Gaughan, Caoimhe / Bhardwaj, Anshul / Sheppard, Andrew D / Bracken-Clarke, Dara / Butler, Christine / Ravi, Narayanasamy / Donohoe, Claire L / Reynolds, John V / Lysaght, Joanne / Conroy, Melissa J

Biomedicines

2024 Volume 12, Issue 4

Abstract: ... therapy and chemokine receptor antagonism impose on T cell phenotypes in OAC with a primary goal ... with healthy controls, anti-tumour T cell function was impaired in OAC patients, demonstrated by lower IFN-γ ...

Abstract	The presence of an immunosuppressive tumour microenvironment in oesophageal adenocarcinoma (OAC) is a major contributor to poor responses. Novel treatment strategies are required to supplement current regimens and improve patient survival. This study examined the immunomodulatory effects that radiation therapy and chemokine receptor antagonism impose on T cell phenotypes in OAC with a primary goal of identifying potential therapeutic targets to combine with radiation to improve anti-tumour responses. Compared with healthy controls, anti-tumour T cell function was impaired in OAC patients, demonstrated by lower IFN-γ production by CD4
Language	English
Publishing date	2024-04-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines12040819
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Article ; Online: Formula supplementation with human and bovine milk oligosaccharides modulates blood IgG and T-helper cell populations, and

Monaco, Marcia H / Wang, Mei / Hauser, Jonas / Yan, Jian / Dilger, Ryan N / Donovan, Sharon M

Frontiers in immunology

2023 Volume 14, Page(s) 1327853

Abstract: ... BMOS. The percentage of PBMC T-helper cells was lower in BMOS+HMO than the other groups. Splenocytes ...

Abstract	Introduction: Human milk contains structurally diverse oligosaccharides (HMO), which are multifunctional modulators of neonatal immune development. Our objective was to investigate formula supplemented with fucosylated (2'FL) + neutral (lacto-N-neotetraose, LNnt) oligosaccharides and/or sialylated bovine milk oligosaccharides (BMOS) on immunological outcomes. Methods: Pigs (n=46) were randomized at 48h of age to four diets: sow milk replacer formula (CON), BMOS (CON + 6.5 g/L BMOS), HMO (CON + 1.0 g/L 2'FL + 0.5 g/L LNnT), or BMOS+HMO (CON + 6.5 g/L BMOS + 1.0 g/L 2'FL + 0.5 g/L LNnT). Blood and tissues were collected on postnatal day 33 for measurement of cytokines and IgG, phenotypic identification of immune cells, and Results: Serum IgG was significantly lower in the HMO group than BMOS+HMO but did not differ from CON or BMOS. The percentage of PBMC T-helper cells was lower in BMOS+HMO than the other groups. Splenocytes from the BMOS group secreted more IL-1β when stimulated Discussion: The addition of a mix of fucosylated and sialylated oligosaccharides to infant formula provides specific activities in the immune system that differ from formulations supplemented with one oligosaccharide structure.
MeSH term(s)	Infant ; Humans ; Animals ; Female ; Swine ; Lipopolysaccharides/analysis ; Leukocytes, Mononuclear ; Oligosaccharides/pharmacology ; Oligosaccharides/chemistry ; Milk, Human/chemistry ; Cytokines/analysis ; T-Lymphocytes, Helper-Inducer ; Dietary Supplements ; Immunoglobulin G/analysis
Chemical Substances	Lipopolysaccharides ; Oligosaccharides ; Cytokines ; Immunoglobulin G
Language	English
Publishing date	2023-12-20
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.2023.1327853
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