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Article ; Online: Emerging strategies for treating autoimmune disorders with genetically modified Treg cells.

Boardman, Dominic A / Levings, Megan K

The Journal of allergy and clinical immunology

2022 Volume 149, Issue 1, Page(s) 1–11

Abstract: Gene editing of living cells is a cornerstone of present-day medical research that has enabled scientists to address fundamental biologic questions and identify novel strategies to treat diseases. The ability to manipulate adoptive cell therapy products ... ...

Abstract	Gene editing of living cells is a cornerstone of present-day medical research that has enabled scientists to address fundamental biologic questions and identify novel strategies to treat diseases. The ability to manipulate adoptive cell therapy products has revolutionized cancer immunotherapy and promises similar results for the treatment of autoimmune diseases, inflammatory disorders, and transplant rejection. Clinical trials have recently deemed polyclonal regulatory T (Treg) cell therapy to be a safe therapeutic option, but questions remain regarding the efficacy of this approach. In this review, we discuss how gene editing technologies are being applied to transform the future of Treg cell therapy, focusing on the preclinical strategies that are currently being investigated to enhance the efficacy, function, and survival of human Treg cells. We explore approaches that may be used to generate immunoregulatory cells ex vivo, detail emerging strategies that are being used to modify these cells (such as using chimeric antigen receptors to confer antigen specificity), and outline concepts that have been explored to repurpose conventional T cells to target and destroy autoreactive and alloreactive lymphocytes. We also describe the key hurdles that currently hinder the clinical adoption of Treg cell therapy and propose potential future avenues of research for this field.
MeSH term(s)	Animals ; Antigens/immunology ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; Autoimmunity ; Humans ; Immunomodulation ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/transplantation
Chemical Substances	Antigens
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
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.2021.11.007
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Article ; Online: Alleviating graft-versus-host disease by directing regulatory T cells to the gut … It is all about location, location, location.

Haque, Manjurul / Boardman, Dominic A / Levings, Megan K

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

2023 Volume 23, Issue 8, Page(s) 1094–1096

Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Editorial
ZDB-ID	2060594-8
ISSN	1600-6143 ; 1600-6135
ISSN (online)	1600-6143
ISSN	1600-6135
DOI	10.1016/j.ajt.2023.04.010
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Article ; Online: Cancer immunotherapies repurposed for use in autoimmunity.

Boardman, Dominic A / Levings, Megan K

Nature biomedical engineering

2019 Volume 3, Issue 4, Page(s) 259–263

MeSH term(s)	Autoimmunity ; Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/therapy
Language	English
Publishing date	2019-04-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-019-0359-6
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Article ; Online: Suppression of Human Dendritic Cells by Regulatory T Cells.

Huang, Qing / Lam, Avery J / Boardman, Dominic A / Dawson, Nicholas A J / Levings, Megan K

Bio-protocol

2021 Volume 11, Issue 21, Page(s) e4217

Abstract: Regulatory T cells (Tregs) suppress immune responses via a variety of mechanisms and can be used as a cellular therapy to induce tolerance. The function of Tregs is commonly assessed in vitro using assays that measure suppression of effector T cell ... ...

Abstract	Regulatory T cells (Tregs) suppress immune responses via a variety of mechanisms and can be used as a cellular therapy to induce tolerance. The function of Tregs is commonly assessed in vitro using assays that measure suppression of effector T cell proliferation and/or cytokine production. However, Tregs can also suppress the function of antigen presenting cells, creating a need for methodology to routinely measure this aspect of their function. This protocol describes a method to measure human Treg-mediated suppression of CD80 and CD86 expression on mature, monocyte-derived dendritic cells. Representative data show suppression mediated by polyclonal Tregs as well as antigen-specific Tregs generated using chimeric antigen receptor (CAR) technology. This method can be used in parallel to T cell suppression assays to measure the functional activity of human Tregs.
Language	English
Publishing date	2021-11-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4217
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Article ; Online: Taking regulatory T-cell therapy one step further.

Sicard, Antoine / Boardman, Dominic A / Levings, Megan K

Current opinion in organ transplantation

2018 Volume 23, Issue 5, Page(s) 509–515

Abstract: Purpose of review: Adoptive cell therapy using CD4FOXP3 regulatory T cells (Treg) has emerged as a promising therapeutic strategy to treat autoimmunity and alloimmunity. Preclinical studies suggest that the efficacy of Treg therapy can be improved by ... ...

Abstract	Purpose of review: Adoptive cell therapy using CD4FOXP3 regulatory T cells (Treg) has emerged as a promising therapeutic strategy to treat autoimmunity and alloimmunity. Preclinical studies suggest that the efficacy of Treg therapy can be improved by modifying the antigen specificity, stability and function of therapeutic Tregs. We review recent innovations that considerably enhance the possibilities of controlling these parameters. Recent findings: Antigen-specific Tregs can be generated by genetically modifying polyclonal Tregs to express designated T-cell receptors or single-chain chimeric antigen receptors. The benefits of this approach can be further extended by using novel strategies to fine-tune the antigen-specificity and affinity of Treg in vivo. CRISPR/Cas 9 technology now enables the modification of therapeutic Tregs so they are safer, more stable and long lived. The differentiation and homing properties of Tregs can also be modulated by gene editing or modifying ex-vivo stimulation conditions. Summary: A new wave of innovation has considerably increased the number of strategies that could be used to increase the therapeutic potential of Treg therapy. However, the increased complexity of these approaches may limit their wide accessibility. Third-party therapy with off-the-shelf Treg products could be a solution.
MeSH term(s)	Animals ; Cell- and Tissue-Based Therapy/methods ; Humans ; Immunotherapy, Adoptive/methods ; T-Lymphocytes, Regulatory/immunology
Language	English
Publishing date	2018-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1390429-2
ISSN	1531-7013 ; 1087-2418
ISSN (online)	1531-7013
ISSN	1087-2418
DOI	10.1097/MOT.0000000000000566
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Article: What Is Direct Allorecognition?

Boardman, Dominic A / Jacob, Jacinta / Smyth, Lesley A / Lombardi, Giovanna / Lechler, Robert I

Current transplantation reports

2016 Volume 3, Issue 4, Page(s) 275–283

Abstract: Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes, typically presented by donor-derived 'passenger' dendritic cells, are recognised directly by recipient T cells. In this review, we ... ...

Abstract	Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes, typically presented by donor-derived 'passenger' dendritic cells, are recognised directly by recipient T cells. In this review, we discuss the two principle theories which have been proposed to explain why individuals possess a high-precursor frequency of T cells with direct allospecificity and how self-restricted T cells recognise allogeneic MHC-peptide complexes. These theories, both of which are supported by functional and structural data, suggest that T cells recognising allogeneic MHC-peptide complexes focus either on the allopeptides bound to the allo-MHC molecules or the allo-MHC molecules themselves. We discuss how direct alloimmune responses may be sustained long term, the consequences of this for graft outcome and highlight novel strategies which are currently being investigated as a potential means of reducing rejection mediated through this pathway.
Language	English
Publishing date	2016-10-07
Publishing country	Switzerland
Document type	Review ; Journal Article
ISSN	2196-3029
ISSN	2196-3029
DOI	10.1007/s40472-016-0115-8
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Article ; Online: Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection.

Rosado-Sánchez, Isaac / Haque, Manjurul / Salim, Kevin / Speck, Madeleine / Fung, Vivian Cw / Boardman, Dominic A / Mojibian, Majid / Raimondi, Giorgio / Levings, Megan K

JCI insight

2023 Volume 8, Issue 19

Abstract: Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding ... ...

Abstract	Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2-specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti-HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.
MeSH term(s)	Mice ; Animals ; Receptors, Chimeric Antigen ; CD28 Antigens ; T-Lymphocytes, Regulatory ; Transplantation, Homologous ; Allografts/metabolism
Chemical Substances	Receptors, Chimeric Antigen ; CD28 Antigens
Language	English
Publishing date	2023-10-09
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.167215
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Article ; Online: Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function.

Peng, Qi / Ratnasothy, Kulachelvy / Boardman, Dominic A / Jacob, Jacinta / Tung, Sim Lai / McCluskey, Daniel / Smyth, Lesley A / Lechler, Robert I / Dorling, Anthony / Lombardi, Giovanna

Frontiers in immunology

2019 Volume 10, Page(s) 1311

Abstract: Regulatory T cells (Tregs) are a subpopulation of T cells that maintain immunological tolerance. In inflammatory responses the function of Tregs is tightly controlled by several factors including signaling through innate receptors such as Toll like ... ...

Abstract	Regulatory T cells (Tregs) are a subpopulation of T cells that maintain immunological tolerance. In inflammatory responses the function of Tregs is tightly controlled by several factors including signaling through innate receptors such as Toll like receptors and anaphylatoxin receptors allowing an effective immune response to be generated. Protease-activated receptors (PARs) are another family of innate receptors expressed on multiple cell types and involved in the pathogenesis of autoimmune disorders. Whether proteases are able to directly modulate Treg function is unknown. Here, we show using two complimentary approaches that signaling through PAR-4 influences the expression of CD25, CD62L, and CD73, the suppressive capacity, and the stability of Tregs
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Cells, Cultured ; Forkhead Transcription Factors/immunology ; Immune Tolerance/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; PTEN Phosphohydrolase/immunology ; Receptors, Thrombin/immunology ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Forkhead Transcription Factors ; Receptors, Thrombin ; PTEN Phosphohydrolase (EC 3.1.3.67) ; protease-activated receptor 4 (JWE1M73YZN)
Language	English
Publishing date	2019-06-18
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.2019.01311
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Article ; Online: MicroRNAs affect dendritic cell function and phenotype.

Smyth, Lesley A / Boardman, Dominic A / Tung, Sim L / Lechler, Robert / Lombardi, Giovanna

Immunology

2014 Volume 144, Issue 2, Page(s) 197–205

Abstract: MicroRNA (miRNA) are small, non-coding RNA molecules that have been linked with immunity through regulating/modulating gene expression. A role for these molecules in T-cell and B-cell development and function has been well established. An increasing body ...

Abstract	MicroRNA (miRNA) are small, non-coding RNA molecules that have been linked with immunity through regulating/modulating gene expression. A role for these molecules in T-cell and B-cell development and function has been well established. An increasing body of literature now highlights the importance of specific miRNA in dendritic cell (DC) development as well as their maturation process, antigen presentation capacity and cytokine release. Given the unique role of DC within the immune system, linking the innate and adaptive immune responses, understanding how specific miRNA affect DC function is of importance for understanding disease. In this review we summarize recent developments in miRNA and DC research, highlighting the requirement of miRNA in DC lineage commitment from bone marrow progenitors and for the development of subsets such as plasmacytoid DC and conventional DC. In addition, we discuss how infections and tumours modulate miRNA expression and consequently DC function.
MeSH term(s)	Animals ; Antigen Presentation/genetics ; Antigen Presentation/immunology ; Cell Differentiation/immunology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Gene Expression Regulation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/immunology ; Humans ; Immune Tolerance/genetics ; Immune Tolerance/immunology ; Mice ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; MicroRNAs/immunology ; Phenotype ; Virus Diseases/immunology
Chemical Substances	MicroRNAs
Language	English
Publishing date	2014-09-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.12390
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Article ; Online: Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection

Isaac Rosado-Sánchez / Manjurul Haque / Kevin Salim / Madeleine Speck / Vivian C.W. Fung / Dominic A. Boardman / Majid Mojibian / Giorgio Raimondi / Megan K. Levings

JCI Insight, Vol 8, Iss

2023 Volume 19

Abstract	Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2–specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti–HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.
Keywords	Immunology ; Transplantation ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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