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LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity
Irina Proekt, … , Mark S. Anderson, Anthony L. DeFranco
Irina Proekt, … , Mark S. Anderson, Anthony L. DeFranco
Published August 29, 2016
Citation Information: J Clin Invest. 2016;126(10):3758-3771. https://doi.org/10.1172/JCI84440.
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Research Article Autoimmunity

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity

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Abstract

Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ-specific autoimmunity in the eye. We further determined that a small pool of retinal protein–specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptibility of autoimmune disease.

Authors

Irina Proekt, Corey N. Miller, Marion Jeanne, Kayla J. Fasano, James J. Moon, Clifford A. Lowell, Douglas B. Gould, Mark S. Anderson, Anthony L. DeFranco

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Figure 5

LYN-deficient DCs from the eye-draining lymph nodes present more IRBP and lead to increased priming of IRBP-specific T cells.

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LYN-deficient DCs from the eye-draining lymph nodes present more IRBP an...
(A) Left: Representative plots showing P2-specific CD4+ T cells in the eye-draining LNs (top) or in pooled peripheral LNs (bottom) from 15- to 20-week-old mice of indicated genotypes, quantified on the right. Each dot represents an individual mouse; horizontal lines show mean; dashed line represents the limit of detection. Data are pooled from 3 independent experiments. (B and C) Fifty thousand P2-specific T cell hybridomas cocultured overnight with DCs from either eye-draining or peripheral LNs from mice of indicated genotypes were analyzed by flow cytometry for CD69 upregulation. As a positive control, 0.1 μg/ml P2 peptide was added. (B) Left: CD69 upregulation by hybridomas cocultured with 200,000 eye-draining LN DCs. Right: CD69 expression (mean fluorescence intensity [MFI]) on hybridomas cocultured with varying numbers of DCs from either eye-draining (filled symbols) or peripheral (open symbols) LNs. As a negative control, anti-MHCII blocking antibody was added to hybridomas cocultured with 200,000 WT DCs. (C) Left: Effects of MHCII blockade on CD69 upregulation by hybridomas cocultured with 100,000 draining LN DCs, quantified over a range of DC concentrations (right). (D) Left: Representative flow cytometry plots showing CD86 and CD8 expression by resident (CD11c+MHCIIint) WT and Lyn–/– cervical LN DCs. Right: CD86 expression on indicated DC populations. Each dot represents an individual mouse; horizontal lines show mean ± SD. (E) Relative cytokine mRNA expression in WT and Lyn–/– sorted resident (CD11c+MHCIIint) LN DCs, normalized to GAPDH, and shown as arbitrary units. Data are representative of at least 3 (B–D) or 2 (E) independent experiments (4–6 mice per group). *P < 0.05, Mann-Whitney test (A). *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA (B and C). *P < 0.05, **P < 0.01, ***P < 0.001, unpaired 2-tailed Student’s t test (D and E).
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