UMMS Affiliation

Department of Medicine, Division of Diabetes; Diabetes Center of Excellence

Publication Date


Document Type



Endocrine System Diseases | Immune System Diseases | Immunity | Immunopathology | Nutritional and Metabolic Diseases


In human type 1 diabetes and animal models of the disease, a diverse assortment of immune cells infiltrates the pancreatic islets. CD8(+) T cells are well represented within infiltrates and HLA multimer staining of pancreas sections provides clear evidence that islet epitope reactive T cells are present within autoimmune lesions. These bona fide effectors have been a key research focus because these cells represent an intellectually attractive culprit for beta cell destruction. However, T cell receptors are highly diverse in human insulitis. This suggests correspondingly broad antigen specificity, which includes a majority of T cells for which there is no evidence of islet-specific reactivity. The presence of "non-cognate" T cells in insulitis raises suspicion that their role could be beyond that of an innocent bystander. In this perspective, we consider the potential pathogenic contribution of non-islet-reactive T cells. Our intellectual framework will be that of a criminal investigation. Having arraigned islet-specific CD8(+) T cells for the murder of pancreatic beta cells, we then turn our attention to the non-target immune cells present in human insulitis and consider the possible regulatory, benign, or effector roles that they may play in disease. Considering available evidence, we overview the case that can be made that non-islet-reactive infiltrating T cells should be suspected as co-conspirators or accessories to the crime and suggest some possible routes forward for reaching a better understanding of their role in disease.


autoreactive T cells, insulitis, non-islet reactive T cells, type 1 diabetes, β cell destruction

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Copyright © 2021 Rodriguez-Calvo, Christoffersson, Bender, von Herrath, Mallone, Kent and James. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

DOI of Published Version



Rodriguez-Calvo T, Christoffersson G, Bender C, von Herrath MG, Mallone R, Kent SC, James EA. Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes? Front Immunol. 2021 Jun 16;12:683091. doi: 10.3389/fimmu.2021.683091. PMID: 34220832; PMCID: PMC8242234. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in immunology

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.