T-cell reactivity to 38 kD insulin-secretory granule protein in patients with recent onset type 1 diabetes

In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

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One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24

10.2337/figshare.13469904.v1 ◽

2021 ◽

Author(s):

Ada Admin ◽

Teresa Rodriguez-Calvo ◽

Lars Krogvold ◽

Natalie Amirian ◽

Knut Dahl-Jørgensen ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Cd8 T Cells ◽

Pancreatic Tissue ◽

Cell Reactivity ◽

Tissue Samples ◽

Recent Onset ◽

Onset Type

In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

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T Cell Reactivity to Human Insulinoma Cell Line (CM) Antigens in Patients with Type 1 Diabetes

Autoimmunity ◽

10.3109/08916939908998532 ◽

1999 ◽

Vol 29 (3) ◽

pp. 171-177 ◽

Cited By ~ 5

Author(s):

L. Monetini ◽

M. g. Cavallo ◽

F. Barone ◽

L. Valente ◽

M. Russo ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Line ◽

Cell Reactivity ◽

Insulinoma Cell ◽

Insulinoma Cell Line ◽

T Cell Reactivity ◽

Human Insulinoma

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Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline

Diabetes ◽

10.2337/db14-0047 ◽

2014 ◽

Vol 63 (10) ◽

pp. 3449-3457 ◽

Cited By ~ 38

Author(s):

T. Orban ◽

C. A. Beam ◽

P. Xu ◽

K. Moore ◽

Q. Jiang ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Subset ◽

Central Memory ◽

C Peptide ◽

Recent Onset ◽

T Cell Subset ◽

Memory T Cell ◽

Onset Type

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T-cell reactivity to insulin peptide A1–12 in children with recently diagnosed type 1 diabetes or multiple β-cell autoantibodies

Journal of Autoimmunity ◽

10.1016/j.jaut.2008.04.024 ◽

2008 ◽

Vol 31 (2) ◽

pp. 142-148 ◽

Cited By ~ 16

Author(s):

Jane Marttila ◽

Suvi Huttunen ◽

Outi Vaarala ◽

Kunimasa Suzuki ◽

John F. Elliott ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Β Cell ◽

Cell Reactivity ◽

T Cell Reactivity

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Mapping T Cell Responses to Native and Neo-Islet Antigen Epitopes in at Risk and Type 1 Diabetes Subjects

Frontiers in Immunology ◽

10.3389/fimmu.2021.675746 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sefina Arif ◽

Irma Pujol-Autonell ◽

Yogesh Kamra ◽

Evangeline Williams ◽

Norkhairin Yusuf ◽

...

Keyword(s):

At Risk ◽

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Single Cell ◽

T Cell Responses ◽

Cell Reactivity ◽

Cell Responses ◽

T Cell Reactivity

AimsRecent studies highlight the potentially important role of neoepitopes in breaking immune tolerance in type 1 diabetes. T cell reactivity to these neoepitopes has been reported, but how this response compares quantitatively and phenotypically with previous reports on native epitopes is not known. Thus, an understanding of the relationship between native and neoepitopes and their role as tolerance breakers or disease drivers in type 1 diabetes is required. We set out to compare T cell reactivity and phenotype against a panel of neo- and native islet autoantigenic epitopes to examine how this relates to stages of type 1 diabetes development.MethodsFifty-four subjects comprising patients with T1D, and autoantibody-positive unaffected family members were tested against a panel of neo- and native epitopes by ELISPOT (IFN-γ, IL-10, and IL-17). A further subset of two patients was analyzed by Single Cell Immune Profiling (RNAseq and TCR α/β) after stimulation with pools of native and neoepitope peptides.ResultsT cell responses to native and neoepitopes were present in patients with type 1 diabetes and at-risk subjects, and overall, there were no significant differences in the frequency, magnitude, or phenotype between the two sets of peptide stimuli. Single cell RNAseq on responder T cells revealed a similar profile in T1D patients stimulated with either neo- or native epitopes. A pro-inflammatory gene expression profile (TNF-α, IFN-γ) was dominant in both native and neoepitope stimulated T cells. TCRs with identical clonotypes were found in T cell responding to both native and neoepitopes.Conclusion/InterpretationThese data suggest that in peripheral blood, T cell responses to both native and neoepitopes are similar in terms of frequency and phenotype in patients with type 1 diabetes and high-risk unaffected family members. Furthermore, using a combination of transcriptomic and clonotypic analyses, albeit using a limited panel of peptides, we show that neoepitopes are comparable to native epitopes currently in use for immune-monitoring studies.

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