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Article ; Online: Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes.

Bettini, Maria / Bettini, Matthew L

2021 Volume 70, Issue 6, Page(s) 1211–1219

Abstract: Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell ( ... ...

Abstract	Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.
MeSH term(s)	Animals ; Autoimmunity/physiology ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/pathology ; Diabetes Mellitus, Type 1/therapy ; Endocrinology/methods ; Endocrinology/trends ; Humans ; Immune Tolerance/physiology ; Immunotherapy, Adoptive/methods ; Immunotherapy, Adoptive/trends ; Mice ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; Pancreas/immunology ; Pancreas/metabolism ; Pancreas/pathology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/physiology ; T-Lymphocytes, Regulatory/transplantation
Language	English
Publishing date	2021-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/dbi18-0058
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Article: The Amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes.

Raugh, Arielle / Jing, Yi / Bettini, Matthew L / Bettini, Maria

Research square

2023

Abstract: Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic ... ...

Abstract	Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic islets is unknown. Within the last decade novel tissue repair functions have been ascribed to Tregs. One function is production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, which promotes tissue repair in response to inflammatory or mechanical tissue injury. Whether such pathways are engaged during autoimmune diabetes and promote tissue repair is undetermined. Previously, we observed upregulation of amphiregulin at the transcriptional level was associated with functional Treg populations in the non-obese diabetic (NOD) mouse model of T1D. We postulated that amphiregulin promoted islet tissue repair and slowed the progression of diabetes in NOD mice. Here, we report that islet-infiltrating Tregs have increased capacity to produce amphiregulin and both Tregs and beta cells express EGFR. Moreover, we show that amphiregulin can directly modulate mediators of endoplasmic reticulum (ER) stress in beta cells. Despite this, NOD amphiregulin deficient mice showed no acceleration of spontaneous autoimmune diabetes. Taken together, the data suggest that the ability for amphiregulin to affect the progression of autoimmune diabetes is limited.
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3204139/v1
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Article ; Online: The amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes.

Raugh, Arielle / Jing, Yi / Bettini, Matthew L / Bettini, Maria

Scientific reports

2023 Volume 13, Issue 1, Page(s) 18653

Abstract: Conventional immunosuppressive functions of ... ...

Abstract	Conventional immunosuppressive functions of CD4
MeSH term(s)	Animals ; Mice ; Amphiregulin/genetics ; Amphiregulin/metabolism ; Diabetes Mellitus, Type 1/metabolism ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Islets of Langerhans/metabolism ; Mice, Inbred NOD ; T-Lymphocytes, Regulatory
Chemical Substances	Amphiregulin ; ErbB Receptors (EC 2.7.10.1) ; Areg protein, mouse ; EGFR protein, mouse (EC 2.7.10.1)
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-45738-4
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Article ; Online: Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function.

Raugh, Arielle / Allard, Denise / Bettini, Maria

Frontiers in immunology

2022 Volume 13, Page(s) 911151

Abstract: The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of ... ...

Abstract	The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of Tregs is still not well understood. Polygenetic susceptibly is a key driving factor in the development of autoimmunity, and many of the pathways implicated in genetic association studies point to a potential alteration or defect in regulatory T cell function. In this review transcriptomic control of Treg development and function is highlighted with a focus on how these pathways are altered during autoimmunity. In combination, observations from autoimmune mouse models and human patients now provide insights into epigenetic control of Treg function and stability. How tissue microenvironment influences Treg function, lineage stability, and functional plasticity is also explored. In conclusion, the current efficacy and future direction of Treg-based therapies for Type 1 Diabetes and other autoimmune diseases is discussed. In total, this review examines Treg function with focuses on genetic, epigenetic, and environmental mechanisms and how Treg functions are altered within the context of autoimmunity.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Diabetes Mellitus, Type 1/immunology ; Forkhead Transcription Factors/genetics ; Humans ; Mice ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; Foxp3 protein, mouse
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.911151
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Article: Increased TCR signaling in regulatory T cells is disengaged from TCR affinity.

Jing, Yi / Kong, Yuelin / Allard, Denise / Liu, Baoyu / Kolawole, Elizabeth / Sprouse, Maran / Evavold, Brian / Bettini, Matthew / Bettini, Maria

bioRxiv : the preprint server for biology

2023

Abstract: Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, TCR affinity and specificities that support Treg function, and how these compare to autoimmune T cells remain unresolved. In this study, we used antigen ... ...

Abstract	Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, TCR affinity and specificities that support Treg function, and how these compare to autoimmune T cells remain unresolved. In this study, we used antigen agnostic and epitope-focused analyses to compare TCR repertoires of regulatory and effector T cells that spontaneously infiltrate pancreatic islets of non-obese diabetic mice. We show that effector and regulatory T cell-derived TCRs possess similar wide-ranging reactivity for self-antigen. Treg-derived TCRs varied in their capacity to confer optimal protective function, and Treg suppressive capacity was in part determined by effector TCR affinity. Interestingly, when expressing the same TCR, Tregs showed higher Nur77-GFP expression than Teffs, suggesting Treg-intrinsic ability to compete for antigen. Our findings provide a new insight into TCR-dependent and independent mechanisms that regulate Treg function and indicate a TCR-intrinsic insufficiency in tissue-specific Tregs that may contribute to the pathogenesis of type 1 diabetes.
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.17.523999
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Article: Understanding Autoimmune Diabetes through the Prism of the Tri-Molecular Complex.

Bettini, Matthew L / Bettini, Maria

Frontiers in endocrinology

2017 Volume 8, Page(s) 351

Abstract: The strongest susceptibility allele for Type 1 Diabetes (T1D) is human leukocyte antigen (HLA), which supports a central role for T cells as the drivers of autoimmunity. However, the precise mechanisms that allow thymic escape and peripheral activation ... ...

Abstract	The strongest susceptibility allele for Type 1 Diabetes (T1D) is human leukocyte antigen (HLA), which supports a central role for T cells as the drivers of autoimmunity. However, the precise mechanisms that allow thymic escape and peripheral activation of beta cell antigen-specific T cells are still largely unknown. Studies performed with the non-obese diabetic (NOD) mouse have challenged several immunological dogmas, and have made the NOD mouse a key experimental system to study the steps of immunodysregulation that lead to autoimmune diabetes. The structural similarities between the NOD I-A
Language	English
Publishing date	2017-12-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2017.00351
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Article ; Online: Immunogen-Specific Strengths and Limitations of the Activation-Induced Marker Assay for Assessing Murine Antigen-Specific CD4+ T Cell Responses.

Nguyen, Nguyen X / Richens, Andrew W / Sircy, Linda M / Allard, Denise E / Kolawole, Elizabeth M / Evavold, Brian D / Bettini, Maria / Hale, J Scott

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 210, Issue 7, Page(s) 916–925

Abstract: The activation-induced marker (AIM) assay is a cytokine-independent technique to identify Ag-specific T cells based on the upregulated expression of activation markers after Ag restimulation. The method offers an alternative to intracellular cytokine ... ...

Abstract	The activation-induced marker (AIM) assay is a cytokine-independent technique to identify Ag-specific T cells based on the upregulated expression of activation markers after Ag restimulation. The method offers an alternative to intracellular cytokine staining in immunological studies, in which limited cytokine production makes the cell subsets of interest difficult to detect. Studies of lymphocytes in human and nonhuman primates have used the AIM assay to detect Ag-specific CD4+ and CD8+ T cells. However, there is a lack of validation of the strengths and limitations of the assay in murine (Mus musculus) models of infection and vaccination. In this study, we analyzed immune responses of TCR-transgenic CD4+ T cells, including lymphocytic choriomeningitis virus-specific SMARTA, OVA-specific OT-II, and diabetogenic BDC2.5-transgenic T cells, and measured the ability of the AIM assay to effectively identify these cells to upregulate AIM markers OX40 and CD25 following culture with cognate Ag. Our findings indicate that the AIM assay is effective for identifying the relative frequency of protein immunization-induced effector and memory CD4+ T cells, whereas the AIM assay had reduced ability to identify specific cells induced by viral infection, particularly during chronic lymphocytic choriomeningitis virus infection. Evaluation of polyclonal CD4+ T cell responses to acute viral infection demonstrated that the AIM assay can detect a proportion of both high- and low-affinity cells. Together, our findings indicate that the AIM assay can be an effective tool for relative quantification of murine Ag-specific CD4+ T cells to protein vaccination, while demonstrating its limitations during conditions of acute and chronic infection.
MeSH term(s)	Mice ; Humans ; Animals ; CD4-Positive T-Lymphocytes ; Antigens ; Lymphocytic choriomeningitis virus ; CD8-Positive T-Lymphocytes ; Cytokines ; Mice, Inbred C57BL
Chemical Substances	Antigens ; Cytokines
Language	English
Publishing date	2023-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200638
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Article ; Online: Generation of T Cell Receptor Retrogenic Mice.

Kong, Yuelin / Jing, Yi / Bettini, Maria

Current protocols in immunology

2019 Volume 125, Issue 1, Page(s) e76

Abstract: The ability to express and study a single T cell receptor (TCR) in vivo is an important aspect of both basic and translational immunological research. Traditionally, this was achieved by using TCR transgenic mice. In the past decade, a more efficient ... ...

Abstract	The ability to express and study a single T cell receptor (TCR) in vivo is an important aspect of both basic and translational immunological research. Traditionally, this was achieved by using TCR transgenic mice. In the past decade, a more efficient approach for single TCR expression was developed. This relatively rapid and accessible method utilizes retrovirus-mediated stem cell-based gene transfer and is commonly referred to as the TCR retrogenic approach. In this approach, hematopoietic bone marrow precursors are transduced with retroviral vector carrying both alpha and beta chains of a T cell receptor. After successful transduction, bone marrow is injected into recipient mice, in which T cell development is driven by expression of the vector-encoded TCR. This article details the materials and methods required to generate TCR retrogenic mice. It is divided into three sections and provides detailed methods for generation of stable retroviral producer cell lines, isolation and optimal transduction of hematopoietic bone marrow cells, and subsequent analysis of TCR retrogenic T cells. A detailed example of such analysis is provided. The current protocol is a culmination of many years of optimization and is the most efficient approach to date. Bone marrow transduction and transfer into recipient mice can now be achieved in a short period of four days. The protocol can be followed in most laboratories with standard biomedical equipment, and is supported by a troubleshooting guide that covers potential pitfalls and unexpected results. © 2019 by John Wiley & Sons, Inc.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Bone Marrow ; Cell Line ; Humans ; Mice ; Receptors, Antigen, T-Cell/genetics ; Retroviridae/genetics ; Transduction, Genetic
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2019-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1934-368X
ISSN (online)	1934-368X
DOI	10.1002/cpim.76
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Article ; Online: Antibody-Mediated Targeting of a Hybrid Insulin Peptide Toward Neonatal Thymic Langerin-Positive Cells Enhances T-Cell Central Tolerance and Delays Autoimmune Diabetes.

Lin, Yong / Perovanovic, Jelena / Kong, Yuelin / Igyarto, Botond Z / Zurawski, Sandra / Tantin, Dean / Zurawski, Gerard / Bettini, Maria / Bettini, Matthew L

Diabetes

2022 Volume 71, Issue 8, Page(s) 1735–1745

Abstract: Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T-cell population. Hybrid peptides formed through transpeptidation within pancreatic β-cell lysosomes have been proposed as a new class of autoantigens in ... ...

Abstract	Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T-cell population. Hybrid peptides formed through transpeptidation within pancreatic β-cell lysosomes have been proposed as a new class of autoantigens in type 1 diabetes (T1D). While the production of hybrid peptides in the thymus has not been explored, due to the nature of their generation, it is thought to be highly unlikely. Therefore, hybrid peptide-reactive thymocytes may preferentially escape thymic selection and contribute significantly to T1D progression. Using an antibody-peptide conjugation system, we targeted the hybrid insulin peptide (HIP) 2.5HIP toward thymic resident Langerin-positive dendritic cells to enhance thymic presentation during the early neonatal period. Our results indicated that anti-Langerin-2.5HIP delivery can enhance T-cell central tolerance toward cognate thymocytes in NOD.BDC2.5 mice. Strikingly, a single dose treatment with anti-Langerin-2.5HIP during the neonatal period delayed diabetes onset in NOD mice, indicating the potential of antibody-mediated delivery of autoimmune neoantigens during early stages of life as a therapeutic option in the prevention of autoimmune diseases.
MeSH term(s)	Animals ; Antibodies ; Autoantigens ; Central Tolerance ; Diabetes Mellitus, Type 1 ; Insulin ; Insulin, Regular, Human ; Mice ; Mice, Inbred NOD ; Peptides ; Thymus Gland
Chemical Substances	Antibodies ; Autoantigens ; Insulin ; Insulin, Regular, Human ; Peptides
Language	English
Publishing date	2022-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db21-1069
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Article ; Online: A dormant T-cell population with autoimmune potential exhibits low self-reactivity and infiltrates islets in type 1 diabetes.

Kong, Yuelin / Jing, Yi / Allard, Denise / Scavuzzo, Marissa A / Sprouse, Maran L / Borowiak, Malgorzata / Bettini, Matthew L / Bettini, Maria

European journal of immunology

2022 Volume 52, Issue 7, Page(s) 1158–1170

Abstract: The contribution of low-affinity T cells to autoimmunity in the context of polyclonal T-cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a ... ...

Abstract	The contribution of low-affinity T cells to autoimmunity in the context of polyclonal T-cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a result, low-affinity T cells are often disregarded as nonantigen-specific cells irrelevant to the immune response. Our study aimed to assess how the level of self-antigen reactivity shapes T-cell lineage and effector responses in the context of spontaneous tissue-specific autoimmunity observed in NOD mice. Using multicolor flow cytometry in combination with Nur77
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes ; Diabetes Mellitus, Type 1 ; Mice ; Mice, Inbred NOD ; Mice, Transgenic ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-04-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149690
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