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Article ; Online: Single-cell analysis implicates T

McCluskey, Daniel / Benzian-Olsson, Natashia / Mahil, Satveer K / Hassi, Niina Karoliina / Wohnhaas, Christian T / Burden, A David / Griffiths, Christopher E M / Ingram, John R / Levell, Nick J / Parslew, Richard / Pink, Andrew E / Reynolds, Nick J / Warren, Richard B / Visvanathan, Sudha / Baum, Patrick / Barker, Jonathan N / Smith, Catherine H / Capon, Francesca

The Journal of allergy and clinical immunology

2022 Volume 150, Issue 4, Page(s) 882–893

Abstract: ... RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant ... overexpression of several T: Conclusions: PPP is associated with complex T-cell activation patterns and ... may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic ...

Abstract	Background: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. Objective: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several T Conclusions: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.
MeSH term(s)	Biological Products ; Cell Plasticity ; Chronic Disease ; Humans ; Leukocytes, Mononuclear/pathology ; Psoriasis ; Quality of Life ; Single-Cell Analysis ; Skin Diseases, Vesiculobullous
Chemical Substances	Biological Products
Language	English
Publishing date	2022-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2022.04.027
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Article: WASP facilitates tumor mechanosensitivity in T lymphocytes.

Mandal, Srishti / Melo, Mariane / Gordiichuk, Pavlo / Acharya, Sayanti / Poh, Yeh-Chuin / Li, Na / Aung, Aereas / Dane, Eric L / Irvine, Darrell J / Kumari, Sudha

bioRxiv : the preprint server for biology

2023

Abstract: Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse ... physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is ... of target cells plays an important role in antigen-triggered T cell responses. However, the molecular ...

Abstract	Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL's mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.02.560434
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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: Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response.

Sharma, Vandana / Kumar, Prabin / Kumar, Rajiv / Chakraborty, Sushmita / Namdeo, Manju / Sazawal, Sudha / Kanga, Uma / Seth, Tulika / Mitra, Dipendra Kumar

Clinical and experimental immunology

2022 Volume 207, Issue 3, Page(s) 272–278

Abstract: ... of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells ... study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T ... and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls ...

Abstract	Acquired aplastic anemia (aAA) is an autoimmune disease, characterized by infiltration of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells. Interferon-gamma (IFN-γ) and perforin are important mediators of cell destruction. In this flow cytometry-based study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T cells in peripheral blood of newly diagnosed aAA patients before and after immunosuppressive therapy (IST). Patients were categorized as per standard disease severity and response to IST. The median percentage of IFN-γ+ and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls. The percentage of these cells was also increased in untreated severe and very severe aplastic anemia when compared with non-severe aplastic anemia patients. In patients before and after IST the median percentage of T cells producing IFN-γ and perforin was elevated in non-responders as compared to partial plus complete responders. The higher percentage of IFN-γ+ and perforin+ CD5+ T cells may be useful as an early diagnostic marker for aberrant activation of immune system and predict poor response to IST in aAA patients, who will benefit from alternative therapy.
MeSH term(s)	Anemia, Aplastic/drug therapy ; Humans ; Interferon-gamma ; Lymphocyte Count ; Perforin ; T-Lymphocytes
Chemical Substances	Perforin (126465-35-8) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2022-03-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxab006
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Article ; Online: Cytoskeletal Control of Antigen-Dependent T Cell Activation.

Colin-York, Huw / Javanmardi, Yousef / Skamrahl, Mark / Kumari, Sudha / Chang, Veronica T / Khuon, Satya / Taylor, Aaron / Chew, Teng-Leong / Betzig, Eric / Moeendarbary, Emad / Cerundolo, Vincenzo / Eggeling, Christian / Fritzsche, Marco

Cell reports

2019 Volume 26, Issue 12, Page(s) 3369–3379.e5

Abstract: Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence ... that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization ... and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell ...

Abstract	Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell receptor and stimulated by a range of antigens, we found that the peak force experienced by the T cell receptor during activation was independent of the unbinding kinetics of the stimulating antigen. Conversely, quantification of the actin retrograde flow velocity at the synapse revealed a striking dependence on the antigen unbinding kinetics. These findings suggest that the dynamics of the actin cytoskeleton actively adjusted to normalize the force experienced by the T cell receptor in an antigen-specific manner. Consequently, tuning actin dynamics in response to antigen kinetics may thus be a mechanism that allows T cells to adjust the lengthscale and timescale of T cell receptor signaling.
MeSH term(s)	Actin Cytoskeleton/immunology ; Humans ; Jurkat Cells ; Lymphocyte Activation ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction/immunology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2019-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.02.074
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Article ; Online: Increased Expression of NOTCH-1 and T Helper Cell Transcription Factors in Patients with Acquired Aplastic Anemia.

Sharma, Vandana / Namdeo, Manju / Kumar, Prabin / Mitra, Dipendra Kumar / Chattopadhyay, Parthaprasad / Sazawal, Sudha / Chaubey, Rekha / Saxena, Renu / Kanga, Uma / Seth, Tulika

Iranian biomedical journal

2022 Volume 27, Issue 6, Page(s) 357–365

Abstract: Background: Acquired aplastic anemia is an autoimmune disease in which auto-aggressive T ... cells destroy hematopoietic progenitors. T-cell differentiation is controlled by transcription factors ... that interact with NOTCH-1, which influences the respective T-cell lineages. Notch signaling also regulates ...

Abstract	Background: Acquired aplastic anemia is an autoimmune disease in which auto-aggressive T cells destroy hematopoietic progenitors. T-cell differentiation is controlled by transcription factors that interact with NOTCH-1, which influences the respective T-cell lineages. Notch signaling also regulates the BM microenvironment. The present study aimed to assess the gene expressions of NOTCH-1 and T helper cell transcription factors in the acquired aplastic anemia patients. Methods: Using quantitative real-time PCR, we studied the mRNA expression level for NOTCH-1, its ligands (DLL-1 and JAG-1), and T helper cell transcription factors (T-BET, GATA-3, and ROR-γt) in both PB and BM of aAA patients and healthy controls. Further, patients of aplastic anemia were stratified by their disease severity as per the standard criteria. Results: The mRNA expression level of NOTCH-1, T-BET, GATA-3, and ROR-γT genes increased in aAA patients compared to healthy controls. There was no significant difference in the mRNA expression of Notch ligands between patients and controls. The mRNA expression level of the above-mentioned genes was found to be higher in SAA and VSAA than NSAA patients. In addition, NOTCH-1 and T helper cell-specific transcription factors enhanced in aAA. We also observed a significant correlation between the genes and hematological parameters in patients. Conclusion: The interaction between NOTCH-1, T-BET, GATA-3, and ROR-γT might lead to the activation, proliferation, and polarization of T helper cells and subsequent BM destruction. The mRNA expression levels of genes varied with disease severity, which may contribute to pathogenesis of aAA.
MeSH term(s)	Humans ; Anemia, Aplastic/genetics ; Anemia, Aplastic/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; RNA, Messenger/genetics ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	Nuclear Receptor Subfamily 1, Group F, Member 3 ; RNA, Messenger ; T-Box Domain Proteins
Language	English
Publishing date	2022-07-31
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2489282-8
ISSN	2008-823X ; 1028-852X
ISSN (online)	2008-823X
ISSN	1028-852X
DOI	10.61186/ibj.3754
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Article ; Online: Cytoskeletal Control of Antigen-Dependent T Cell Activation

Huw Colin-York / Yousef Javanmardi / Mark Skamrahl / Sudha Kumari / Veronica T. Chang / Satya Khuon / Aaron Taylor / Teng-Leong Chew / Eric Betzig / Emad Moeendarbary / Vincenzo Cerundolo / Christian Eggeling / Marco Fritzsche

Cell Reports, Vol 26, Iss 12, Pp 3369-3379.e

2019 Volume 5

Abstract: Summary: Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence ... that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization ... and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell ...

Abstract	Summary: Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell receptor and stimulated by a range of antigens, we found that the peak force experienced by the T cell receptor during activation was independent of the unbinding kinetics of the stimulating antigen. Conversely, quantification of the actin retrograde flow velocity at the synapse revealed a striking dependence on the antigen unbinding kinetics. These findings suggest that the dynamics of the actin cytoskeleton actively adjusted to normalize the force experienced by the T cell receptor in an antigen-specific manner. Consequently, tuning actin dynamics in response to antigen kinetics may thus be a mechanism that allows T cells to adjust the lengthscale and timescale of T cell receptor signaling. : T cell activation relies on a dynamic actin cytoskeleton. Here, Colin-York et al. show how the kinetics of the stimulating antigen influence the dynamics of actin. This feedback mechanism influences the mechanics at the immune synapse, allowing T cells to orchestrate the length scale and timescale of signaling. Keywords: TFM, actin dynamics, TCR cluster, immunological synapse, mechanosensation, mechanosensitivity, T cell activation
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch.

Tu, Wen Juan / McCuaig, Robert D / Tan, Abel H Y / Hardy, Kristine / Seddiki, Nabila / Ali, Sayed / Dahlstrom, Jane E / Bean, Elaine G / Dunn, Jenny / Forwood, Jade / Tsimbalyuk, Sofia / Smith, Kate / Yip, Desmond / Malik, Laeeq / Prasanna, Thiru / Milburn, Peter / Rao, Sudha

Frontiers in immunology

2020 Volume 11, Page(s) 1228

Abstract: Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here ... ...

Abstract	Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1
MeSH term(s)	Animals ; Biomarkers ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Line, Tumor ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cellular Reprogramming/drug effects ; Cellular Reprogramming/genetics ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene Expression ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Humans ; Immunotherapy ; Mice ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome
Chemical Substances	Biomarkers ; EOMES protein, human ; T-Box Domain Proteins ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-)
Language	English
Publishing date	2020-06-16
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.2020.01228
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Article ; Online: Enhanced Therapeutic Efficacy and Memory of Tumor-Specific CD8 T Cells by

Abu Eid, Rasha / Ahmad, Shamim / Lin, Yuan / Webb, Mason / Berrong, Zuzana / Shrimali, Rajeev / Kumai, Takumi / Ananth, Sudha / Rodriguez, Paulo C / Celis, Esteban / Janik, John / Mkrtichyan, Mikayel / Khleif, Samir N

Cancer research

2017 Volume 77, Issue 15, Page(s) 4135–4145

Abstract: Inhibition of specific Akt isoforms in ... ...

Abstract	Inhibition of specific Akt isoforms in CD8
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/enzymology ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Immunologic Memory/immunology ; Immunotherapy, Adoptive/methods ; Lymphocyte Activation/immunology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Chemical Substances	Enzyme Inhibitors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Pik3cd protein, mouse (EC 2.7.1.137)
Language	English
Publishing date	2017-08-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-16-1925
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Article ; Online: Cytoskeletal tension actively sustains the migratory T-cell synaptic contact.

Kumari, Sudha / Mak, Michael / Poh, Yeh-Chuin / Tohme, Mira / Watson, Nicki / Melo, Mariane / Janssen, Erin / Dustin, Michael / Geha, Raif / Irvine, Darrell J

The EMBO journal

2020 Volume 39, Issue 5, Page(s) e102783

Abstract: When migratory T cells encounter antigen-presenting cells (APCs), they arrest and form radially ... biochemical information and are critical for T-cell immunity. While the cellular processes underlying synapse ... of the synapse, remain unknown. Here we identify an antigen-triggered mechanism that actively promotes T-cell ...

Abstract	When migratory T cells encounter antigen-presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T-cell immunity. While the cellular processes underlying synapse formation have been well characterized, those that maintain the symmetry, and thereby the stability of the synapse, remain unknown. Here we identify an antigen-triggered mechanism that actively promotes T-cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott-Aldrich syndrome protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T-cell activation, WASP is degraded, leading to cytoskeletal unraveling and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell-APC synaptic contact.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/metabolism ; Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Cell Movement ; Cytoskeleton/metabolism ; Humans ; Immunological Synapses/metabolism ; Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Wiskott-Aldrich Syndrome/immunology ; Wiskott-Aldrich Syndrome/metabolism ; Wiskott-Aldrich Syndrome Protein/genetics ; Wiskott-Aldrich Syndrome Protein/metabolism
Chemical Substances	Actins ; WAS protein, human ; Wiskott-Aldrich Syndrome Protein
Language	English
Publishing date	2020-01-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2019102783
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