Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.
Proc Natl Acad Sci U S A
; 121(20): e2320268121, 2024 May 14.
Article
em En
| MEDLINE
| ID: mdl-38709934
ABSTRACT
Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Timo
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Receptores de Antígenos de Linfócitos T
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Proteína AIRE
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Insulina
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article