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Apaolaza Gallegos, S.P. ; Balcacean, D. ; Zapardiel-Gonzalo, J. ; Rodriguez-Calvo, T.

The extent and magnitude of islet T cell infiltration as powerful tools to define the progression to type 1 diabetes.

Diabetologia 66, 1129-1141 (2023)

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AIMS/HYPOTHESIS: Insulitis is not present in all islets, and it is elusive in humans. Although earlier studies focused on islets that fulfilled certain criteria (e.g. ≥15 CD45⁺ cells or ≥6 CD3⁺ cells), there is a fundamental lack of understanding of the infiltration dynamics in terms of its magnitude (i.e. how much) and extent (i.e. where). Here, we aimed to perform an in-depth characterisation of T cell infiltration by investigating islets with moderate (1-5 CD3⁺ cells) and high (≥6 CD3⁺ cells) infiltration in individuals with and without type 1 diabetes. METHODS: Pancreatic tissue sections from 15 non-diabetic, eight double autoantibody-positive and ten type 1 diabetic (0-2 years of disease duration) organ donors were obtained from the Network for Pancreatic Organ Donors with Diabetes, and stained for insulin, glucagon, CD3 and CD8 by immunofluorescence. T cell infiltration was quantified in a total of 8661 islets using the software QuPath. The percentage of infiltrated islets and islet T cell density were calculated. To help standardise the analysis of T cell infiltration, we used cell density data to develop a new T cell density threshold capable of differentiating non-diabetic and type 1 diabetic donors. RESULTS: Our analysis revealed that 17.1% of islets in non-diabetic donors, 33% of islets in autoantibody-positive and 32.5% of islets in type 1 diabetic donors were infiltrated by 1 to 5 CD3⁺ cells. Islets infiltrated by ≥6 CD3⁺ cells were rare in non-diabetic donors (0.4%) but could be found in autoantibody-positive (4.5%) and type 1 diabetic donors (8.2%). CD8⁺ and CD8^- populations followed similar patterns. Likewise, T cell density was significantly higher in the islets of autoantibody-positive donors (55.4 CD3⁺ cells/mm²) and type 1 diabetic donors (74.8 CD3⁺ cells/mm²) compared with non-diabetic individuals (17.3 CD3⁺ cells/mm²), which was accompanied by higher exocrine T cell density in type 1 diabetic individuals. Furthermore, we showed that the analysis of a minimum of 30 islets and the use of a reference mean value for T cell density of 30 CD3⁺ cells/mm² (the 30-30 rule) can differentiate between non-diabetic and type 1 diabetic donors with high specificity and sensitivity. In addition, it can classify autoantibody-positive individuals as non-diabetic or type 1 diabetic-like. CONCLUSIONS/INTERPRETATION: Our data indicates that the proportion of infiltrated islets and T cell density change dramatically during the course of type 1 diabetes, and these changes can be already observed in double autoantibody-positive individuals. This suggests that, as disease progresses, T cell infiltration extends throughout the pancreas, reaching the islets and exocrine compartment. While it predominantly targets insulin-containing islets, large accumulations of cells are rare. Our study fulfils the need to further understand T cell infiltration, not only after diagnosis but also in individuals with diabetes-related autoantibodies. Furthermore, the development and application of new analytical tools based on T cell infiltration, like the 30-30 rule, will allow us to correlate islet infiltration with demographic and clinical variables with the aim of identifying individuals at the very early stages of the disease.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cell Density ; Image Analysis ; Infiltration ; Insulitis ; Islets ; Pancreas ; Pathology ; T Cells ; Type 1 Diabetes; Insulitis; Onset; Pathogenesis; Mass

ISSN (print) / ISBN 0012-186X

e-ISSN 1432-0428

Journal Diabetologia

Quellenangaben Volume: 66, Issue: 6, Pages: 1129-1141

Publisher Springer

Publishing Place Berlin ; Heidelberg [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes Research Type 1 (IDF)

Grants Leona M. and Harry B. Helmsley Charitable Trust
EFPIA
Union's Horizon 2020 research and innovation programme
IMI2-JU
JDRF
Projekt DEAL