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A dormant T cell population with autoimmune potential exhibits low self-reactivity and infiltrates islets in type I diabetes

ABSTRACT: T cells have been established as the key drivers of autoimmune diabetes. However, it is unknown whether all T cells that infiltrate the pancreas are equally pathogenic, and how the level of reactivity for self-antigen modulates differentiation and pathogenic potential of effector T cells. Moreover, the contribution of bystander, non-antigen reactive T cells in islet autoimmunity has not been resolved. Using multi-color flow cytometry in combination with Nur77-GFP reporter of TCR signaling we identified a “dormant” population of CD4+ T cells that infiltrate the islets of pre-diabetic NOD mice and constitute a significant proportion of all islet infiltrating T cells (~47%). We analyzed TCR repertoire, transcriptional profile, effector function, and autoimmune potential of this subpopulation. This T cell population, characterized by low level expression of CD5 and a unique TCR repertoire, exhibited central memory phenotype with reduced activation and effector function; however, induced rapid diabetes upon transfer. Overall, our study suggests that the strength of reactivity for tissue antigen dictates the level of T cell activation and differentiation; however, cells with low level of TCR signaling and reactivity for islet antigen infiltrating the pancreas of NOD mice are pathogenic and are capable of inducing beta cell destruction.

ORGANISM(S): Mus musculus

PROVIDER: GSE131345 | GEO | 2019/05/17

REPOSITORIES: GEO

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Increased β-cell proliferation prior to immune-cell invasion prevents progression of type 1 diabetes

Project description:Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass in female NOD mice early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. We observed that a model exhibiting β-cell hyperplasia on the NOD background (NOD-LIRKO) displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely, similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with a downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data provide novel evidence that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

2019-03-29 | GSE128315 | GEO

Transcriptional analysis of type 1 diabetes reveals an interferon signature that precedes T cell activation

Project description:Type 1 diabetes (T1D) is an autoimmune disease triggered by T cell reactivity to protein antigens produced by the β-cells. Here we present a chronological compendium of transcriptional profiles from islets of Langerhans isolated from non-obese diabetic (NOD) mice ranging from 2 wks up to diabetes and compared to controls. Parallel analysis was made of cellular components of the islets. Myeloid cells populated the islets early during development in all mouse strains. This was followed by a type I interferon signature detectable at 4-6 wks of age only in diabetes susceptible mice. Concurrently, CD4 T cells were found within islets, many in contact with intra-islet antigen presenting cells. Early cellular signs of islet reactivity were detected by six wks. By 8 wks, NOD islets contained all major leukocytes populations and an inflammatory gene signature. This work establishes the natural transcriptional signature of T1D and provides a resource for future research. 57 RNA samples isolated from the pancreatic islets of langerhans of experimental mice: 2-18 wk old non-obese diabetic (NOD) and newly diabetic NOD were compared to controls: NOD.RAG-/-, B6.g7 and C57BL/6. There were 3 or 6 biological replicates per condition. All mice were female. All data was normalized using RMA in Arraystar. Data table includes normalized probe intensity for every probe.

2013-01-28 | E-GEOD-41203 | biostudies-arrayexpress

A critical insulin TCR contact residue selects high affinity and pathogenic insulin specific T cells

Project description:Type 1 Diabetes (T1D) is an autoimmune mediated disease that culminates in the targeted destruction of insulin producing β cells. CD4 responses in non-obese diabetic mice are dominated by InsB9-23 specificity, and mutation of the key TCR contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and T regulatory cells. Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality and pathogenicity of insulin specific T cells that develop in the absence of cognate antigen. Using single TCR system, we demonstrate that Treg development is greatly diminished in mice with Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB9-23 by both limiting the development of pathogenic T cells and supporting the selection of regulatory T cells.

2019-10-30 | GSE139544 | GEO

Transcriptional analysis of type 1 diabetes reveals an interferon signature that precedes T cell activation

2013-01-28 | GSE41203 | GEO

Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes

Project description:In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD CD28-/- mice. InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, while whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

2023-07-24 | GSE238146 | GEO

Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

Project description:The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in inflammatory disease models. The differential ability of Tc17 differentiation was not related to T-cell receptor (TCR) diversity and antigen specificity but was inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon was linked to differential levels of intrinsic TCR sensitivity and basal SMAD3 expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

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RNA-seq of islet-specific CD8 T cells in the spleen and pancreatic islets

Project description:T cells infiltrate pancreatic islets during the progression of type 1 diabetes (T1D) but their differentiation states have not been completely defined. We used unbiased single-cell RNA sequencing analyses to gain further insight into the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In CD8 T cells, we identified two activated subsets in addition to naïve cells. The two activated islet CD8 T cell subsets respectively resemble the self-renewing progenitor cells and the terminally differentiated/exhausted effectors during chronic lymphocytic choriomeningitis virus infection. We also identified a BATF-driven transcriptional signature promoting the diabetogenic activity of islet-infiltrating β cell autoreactive CD8 T effectors. Our results provide a useful resource for understanding T cell differentiation programs in T1D.

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RNA-seq of BATF-overexpressing CD8 T cells in vitro

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T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)

Project description:The presented data corresponds to the analysis of two discrete subsets of human CD8+ naive T cells, defined by positive and negative expression of the chemokine receptor CXCR3 (TNR3-, TNR3+). In this study we demonstrated that these subsets have different potential to generate fully-differentiated effector T cells following antigen-specific stimulation. The performed systematic immune repertoire analysis (T cell receptor beta chain (TRB)) of the sorted cell subsets revealed diverse physico-chemical properties of TRB CDR3 sequences suggesting enhanced TCR self-reactivity in human TNR3+ cells. In total, we analyzed 74 samples (from 11 patients, 3 replicates of each cell subset (excluding one missing replicate) and additionally for 3 patients CD8+ memory T cells in 3 replicates). We used the Human TCR Profiling Kit (MiLaboratory LLC) for sequencing libraries preparation and Illumina NextSeq 550 sequencing (150+150bp) followed by the demultiplexing procedure using MIGEC software (https://github.com/mikessh/migec).

2019-10-17 | E-MTAB-7638 | biostudies-arrayexpress

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