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Article ; Online: Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells.

Shapiro, Melanie R / Peters, Leeana D / Brown, Matthew E / Cabello-Kindelan, Cecilia / Posgai, Amanda L / Bayer, Allison L / Brusko, Todd M

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 7, Page(s) 1108–1122

Abstract: IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of ... ...

Abstract	IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1 receptor was elevated on murine memory and human naive Treg subsets. IL-2 and IGF1 promoted PI3K/Akt signaling in Tregs, inducing thymically-derived Treg expansion beyond either agent alone in NOD mice. Increased populations of murine Tregs of naive or memory, as well as CD5lo polyclonal or CD5hi likely self-reactive, status were also observed. Expansion was attributed to increased IL-2Rγ subunit expression on murine Tregs exposed to IL-2 and IGF1 as compared with IL-2 or IGF1 alone. Assessing translational capacity, incubation of naive human CD4+ T cells with IL-2 and IGF1 enhanced thymically-derived Treg proliferation in vitro, without the need for TCR ligation. We then demonstrated that IGF1 and IL-2 or IL-7, which is also IL-2Rγ-chain dependent, can be used to induce proliferation of genetically engineered naive human Tregs or T conventional cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive homeostatic T cell expansion, both in vitro and in vivo, for cellular therapeutics and ex vivo gene editing.
MeSH term(s)	Humans ; Animals ; Mice ; Mice, Inbred NOD ; Insulin-Like Growth Factor I ; T-Lymphocytes, Regulatory ; Interleukin-2 ; Phosphatidylinositol 3-Kinases ; Cell Proliferation
Chemical Substances	Insulin-Like Growth Factor I (67763-96-6) ; Interleukin-2 ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2023-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
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.2200651
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Article ; Online: Pleiotropic roles of the insulin-like growth factor axis in type 1 diabetes.

Shapiro, Melanie R / Atkinson, Mark A / Brusko, Todd M

Current opinion in endocrinology, diabetes, and obesity

2019 Volume 26, Issue 4, Page(s) 188–194

Abstract: Purpose of review: We review studies demonstrating lowered levels of insulin-like growth factors (IGFs) in patients with recent-onset type 1 diabetes (T1D) and discuss their potential roles in the disorder's pathogenesis.: Recent findings: IGFs have ... ...

Abstract	Purpose of review: We review studies demonstrating lowered levels of insulin-like growth factors (IGFs) in patients with recent-onset type 1 diabetes (T1D) and discuss their potential roles in the disorder's pathogenesis. Recent findings: IGFs have long been recognized as a class of hormones that promote growth, development, and cellular metabolism throughout the human body. More recently, studies have noted an association between reduced pancreatic weight/volume and T1D. Thus, we believe it is important to understand pancreatic regulation of IGF expression and bioavailability, as well as the impact of IGFs on pancreatic growth and islet health. Additional studies of IGFs have been extended to their influence on the inflammatory/regulatory balance of monocytes, B cells, and T cells; features which have been previously established to show dysregulation in settings of T1D. Summary: These data suggest that IGFs may prevent known impairments in the pancreas and immune system in T1D and underscore the need to extend these studies, some of which were performed in health or other autoimmune diseases, toward T1D specifically. Collectively, the work emphasized here support the potential therapeutic use of IGFs in T1D prevention efforts as pancreatic growth factors and/or immunoregulatory agents.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 1/etiology ; Diabetes Mellitus, Type 1/immunology ; Humans ; Pancreas/physiology ; Somatomedins/physiology
Chemical Substances	Somatomedins
Language	English
Publishing date	2019-05-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2272017-0
ISSN	1752-2978 ; 1752-296X
ISSN (online)	1752-2978
ISSN	1752-296X
DOI	10.1097/MED.0000000000000484
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Article ; Online: The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes.

Sharp, Robert C / Brown, Matthew E / Shapiro, Melanie R / Posgai, Amanda L / Brusko, Todd M

Frontiers in immunology

2021 Volume 12, Page(s) 739048

Abstract: Background: The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants ... ...

Abstract	Background: The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin ( Scope of review: In this review, we summarize the literature related to the T1D-associated risk variants in Major conclusions: We propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Antigens, Differentiation/genetics ; Antigens, Differentiation/metabolism ; CD47 Antigen/metabolism ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/therapy ; Genetic Association Studies ; Humans ; Immunotherapy ; Insulin-Secreting Cells/immunology ; Insulin-Secreting Cells/metabolism ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Polymorphism, Genetic ; Receptors, Cell Surface/metabolism ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Antigens, Differentiation ; CD47 Antigen ; CD47 protein, human ; Receptors, Cell Surface ; Receptors, Immunologic ; SIRPA protein, human ; SIRPB1 protein, human ; SIRPG protein, human
Language	English
Publishing date	2021-09-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.739048
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Article ; Online: Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.

Thirawatananond, Puchong / Brown, Matthew E / Sachs, Lindsey K / Arnoletti, Juan M / Yeh, Wen-I / Posgai, Amanda L / Shapiro, Melanie R / Chen, Yi-Guang / Brusko, Todd M

Diabetes

2023 Volume 72, Issue 11, Page(s) 1629–1640

Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db23-0307
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Article ; Online: De-coding genetic risk variants in type 1 diabetes.

Shapiro, Melanie R / Thirawatananond, Puchong / Peters, Leeana / Sharp, Robert C / Ogundare, Similoluwa / Posgai, Amanda L / Perry, Daniel J / Brusko, Todd M

Immunology and cell biology

2021 Volume 99, Issue 5, Page(s) 496–508

Abstract: The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene ... ...

Abstract	The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 1/genetics ; Genetic Predisposition to Disease ; Genotype ; Mice ; Mice, Inbred NOD ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12438
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Article ; Online: Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

Redondo, Maria J / Harrall, Kylie K / Glueck, Deborah H / Tosur, Mustafa / Uysal, Serife / Muir, Andrew / Atkinson, Elizabeth G / Shapiro, Melanie R / Yu, Liping / Winter, William E / Weedon, Michael / Brusko, Todd M / Oram, Richard / Vehik, Kendra / Hagopian, William / Atkinson, Mark A / Dabelea, Dana

Diabetes/metabolism research and reviews

2023 Volume 40, Issue 3, Page(s) e3744

Abstract: Aims: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) ... ...

Abstract	Aims: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. Materials and methods: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. Results: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. Conclusions: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.
MeSH term(s)	Child ; Adolescent ; Humans ; Young Adult ; Adult ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 1/complications ; Ethnicity ; Cross-Sectional Studies ; Prospective Studies
Language	English
Publishing date	2023-10-27
Publishing country	England
Document type	Observational Study ; Multicenter Study ; Journal Article
ZDB-ID	1470192-3
ISSN	1520-7560 ; 1520-7552
ISSN (online)	1520-7560
ISSN	1520-7552
DOI	10.1002/dmrr.3744
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Article ; Online: Human CD4

Brown, Matthew E / Peters, Leeana D / Hanbali, Seif R / Arnoletti, Juan M / Sachs, Lindsey K / Nguyen, Kayla Q / Carpenter, Emma B / Seay, Howard R / Fuhrman, Christopher A / Posgai, Amanda L / Shapiro, Melanie R / Brusko, Todd M

Frontiers in immunology

2022 Volume 13, Page(s) 873560

Abstract: Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a ... ...

Abstract	Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4
MeSH term(s)	Autoimmune Diseases ; Cell- and Tissue-Based Therapy ; Cytokines/metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Interferon-gamma ; T-Lymphocytes, Regulatory
Chemical Substances	Cytokines ; Forkhead Transcription Factors ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2022-05-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.2022.873560
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Article ; Online: Human immune phenotyping reveals accelerated aging in type 1 diabetes.

JCI insight

2023 Volume 8, Issue 17

Abstract: The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We ... ...

Abstract	The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals (stage 3 T1D, their first-degree relatives, those with ≥2 islet autoantibodies, and autoantibody-negative unaffected controls). We constructed an immune age predictive model in unaffected participants and observed accelerated immune aging in T1D. We used generalized additive models for location, shape, and scale to obtain age-corrected data for flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and programmed cell death 1-positive (PD-1+) frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels on memory T cells. Phenotypes associated with T1D after age correction were predictive of T1D status. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.
MeSH term(s)	Humans ; Infant ; Diabetes Mellitus, Type 1 ; Cross-Sectional Studies ; Programmed Cell Death 1 Receptor ; Autoantibodies ; Aging
Chemical Substances	Programmed Cell Death 1 Receptor ; Autoantibodies
Language	English
Publishing date	2023-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.170767
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Article ; Online: A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes.

Shapiro, Melanie R / Foster, Timothy P / Perry, Daniel J / Rosenfeld, Ron G / Dauber, Andrew / McNichols, James A / Muir, Andrew / Hwa, Vivian / Brusko, Todd M / Jacobsen, Laura M

Hormone research in paediatrics

2020 Volume 93, Issue 5, Page(s) 322–334

Abstract: Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, ... ...

Abstract	Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. Case presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.
MeSH term(s)	CD4 Lymphocyte Count ; Case-Control Studies ; Codon, Nonsense ; Congenital Abnormalities/genetics ; Congenital Abnormalities/immunology ; Failure to Thrive/genetics ; Female ; Humans ; Hypoglycemia/genetics ; Infant, Newborn ; Infant, Premature ; Leukocytes, Mononuclear/metabolism ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Twins
Chemical Substances	Codon, Nonsense ; IGF1R protein, human ; Receptor, IGF Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2020-10-28
Publishing country	Switzerland
Document type	Case Reports ; Journal Article
ZDB-ID	2537278-6
ISSN	1663-2826 ; 1663-2818
ISSN (online)	1663-2826
ISSN	1663-2818
DOI	10.1159/000510764
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Article: Intestinal Epithelial Cell Regulation of Adaptive Immune Dysfunction in Human Type 1 Diabetes.

Graves, Christina L / Li, Jian / LaPato, Melissa / Shapiro, Melanie R / Glover, Sarah C / Wallet, Mark A / Wallet, Shannon M

Frontiers in immunology

2017 Volume 7, Page(s) 679

Abstract: Environmental factors contribute to the initiation, progression, and maintenance of type 1 diabetes (T1D), although a single environmental trigger for disease has not been identified. Studies have documented the contribution of immunity within the ... ...

Abstract	Environmental factors contribute to the initiation, progression, and maintenance of type 1 diabetes (T1D), although a single environmental trigger for disease has not been identified. Studies have documented the contribution of immunity within the gastrointestinal tract (GI) to the expression of autoimmunity at distal sites. Intestinal epithelial cells (IECs) regulate local and systemic immunologic homeostasis through physical and biochemical interactions with innate and adaptive immune populations. We hypothesize that a loss in the tolerance-inducing nature of the GI tract occurs within T1D and is due to altered IECs' innate immune function. As a first step in addressing this hypothesis, we contrasted the global immune microenvironment within the GI tract of individuals with T1D as well as evaluated the IEC-specific effects on adaptive immune cell phenotypes. The soluble and cellular immune microenvironment within the duodenum, the soluble mediator profile of primary IECs derived from the same duodenal tissues, and the effect of the primary IECs' soluble mediator profile on T-cell expansion and polarization were evaluated. Higher levels of IL-17C and beta-defensin 2 (BD-2) mRNA in the T1D-duodenum were observed. Higher frequencies of type 1 innate lymphoid cells (ILC1) and CD8+CXCR3+ T-cells (Tc1) were also observed in T1D-duodenal tissues, concomitant with lower frequencies of type 3 ILC (ILC3) and CD8+CCR6+ T-cells (Tc17). Higher levels of proinflammatory mediators (IL-17C and BD-2) in the absence of similar changes in mediators associated with homeostasis (interleukin 10 and thymic stromal lymphopoietin) were also observed in T1D-derived primary IEC cultures. T1D-derived IEC culture supernatants induced more robust CD8+ T-cell proliferation along with enhanced polarization of Tc1 populations, at the expense of Tc17 polarization, as well as the expansion of CXCR3+CCR6+/- Tregs, indicative of a Th1-like and less regulatory phenotype. These data demonstrate a proinflammatory microenvironment of the T1D-duodenum, whereby IECs have the potential to contribute to the expansion and polarization of innate and adaptive immune cells. Although these data do not discern whether these observations are not simply a consequence of T1D, the data indicate that the T1D-GI tract has the capacity to foster a permissive environment under which autoreactive T-cells could be expanded and polarized.
Language	English
Publishing date	2017-01-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2016.00679
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