Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.
Proc Natl Acad Sci U S A
; 121(5): e2311487121, 2024 Jan 30.
Article
en En
| MEDLINE
| ID: mdl-38261611
ABSTRACT
Roughly one-half of mice with partial defects in two immune tolerance pathways (AireGW/+Lyn-/- mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid-binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4+ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP-/- mice and greatly defective in AireGW/+ mice. Most P2.U2+/- mice and all P2.U.2+/-AireGW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.
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1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores de Antígenos de Linfocitos T
/
Presentación de Antígeno
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2024
Tipo del documento:
Article