Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it?

Hull, Caroline; Peakman, Mark; Tree, Timothy

doi:10.1007/s00125-017-4377-1

Cited by 134 publications

(114 citation statements)

References 109 publications

(104 reference statements)

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“…A) . There is still no consensus on whether T reg cell frequencies correlate with T1D onset . Furthermore, some have argued that T eff cells from diabetic subjects are resistant to suppression by T reg cells , possibly through a STAT‐3‐dependent mechanism .…”

Section: Treg Cell Dysfunction In Human Diseasementioning

confidence: 99%

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Attias

Al-Aubodah

Piccirillo

2019

Clinical and Experimental Immunology

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Summary Regulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage‐defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non‐suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen‐specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.

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Section: Treg Cell Dysfunction In Human Diseasementioning

confidence: 99%

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Attias

Al-Aubodah

Piccirillo

2019

Clinical and Experimental Immunology

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“…People with type 1 diabetes display altered frequencies and function of a number of lymphocyte subsets, as well as different expression levels of surface markers; frequency and suppressive ability of Tregs are reduced in type 1 diabetes [3]. Expression of C-X-C motif chemokine receptor 3 (CXCR3) is reduced on CD3 + T cells in individuals with long-standing type 1 diabetes [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

et al. 2020

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Aims/hypothesis The aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes. Methods Immunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8 + T cells were quantified using peptide-HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs. Results Islet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4 + and CD8 + T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4 + T cells with a central memory phenotype (CD27 int , CD127 + , CD95 int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4 + T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8 + T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06). Conclusions/interpretation In this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications.

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“…In conclusion, our study indicated that T1D with IPEX is principally caused by Treg dysfunction and can be improved by early intervention with HSCT. Recent studies suggested that reduction in the functional capacity of Treg populations contributes to autoimmune disease development in T1D . We hypothesize that early intervention with HSCT before or following onset of DM can improve several symptoms of IPEX caused by various autoimmunity diseases including T1D.…”

Section: Discussionmentioning

confidence: 88%

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

et al. 2019

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Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.

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Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it?

Cited by 134 publications

References 109 publications

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

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