Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes?

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 pres...

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Published in:Frontiers in immunology Vol. 12; p. 683091
Main Authors: Rodriguez-Calvo, Teresa, Christoffersson, Gustaf, Bender, Christine, von Herrath, Matthias G., Mallone, Roberto, Kent, Sally C., James, Eddie A.
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 16.06.2021
Subjects:
Animals
Autoimmunity - genetics
Autoimmunity - immunology
autoreactive T cells
beta cell destruction
Biomarkers
Cell Communication - genetics
Cell Communication - immunology
Cellular Microenvironment - immunology
Diabetes Mellitus, Type 1 - etiology
Diabetes Mellitus, Type 1 - metabolism
Diabetes Mellitus, Type 1 - pathology
Disease Models, Animal
Disease Susceptibility
Humans
Immunology
insulitis
Islets of Langerhans - immunology
Islets of Langerhans - metabolism
Islets of Langerhans - pathology
non-islet reactive T cells
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocyte Subsets - pathology
type 1 diabetes
β cell destruction
β cell destruction
type 1 diabetes
insulitis
non-islet reactive T cells
autoreactive T cells
ISSN:1664-3224, 1664-3224
Online Access:Get full text
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Summary: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 β 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 β 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.
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This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
Edited by: Linda L. Kusner, George Washington University, United States
Reviewed by: Helen Thomas, University of Melbourne, Australia; Nick Giannoukakis, Allegheny Health Network, United States; Hans Dooms, Boston University, United States
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.683091