Defective selection of thymic regulatory T cells accompanies autoimmunity and pulmonary infiltrates in Tcra-deficient mice double transgenic for human La/Sjögren's syndrome-B and human La-specific TCR.
Jane C YaciukYujun PanKaren SchwarzZi-Jian PanJacen S Maier-MooreStanley D KosankeChristina LawrenceAmy Darise FarrisPublished in: Journal of immunology (Baltimore, Md. : 1950) (2015)
A human La/Sjögren's syndrome-B (hLa)-specific TCR/hLa neo-self-Ag double-transgenic (Tg) mouse model was developed and used to investigate cellular tolerance and autoimmunity to the ubiquitous RNA-binding La Ag often targeted in systemic lupus erythematosus and Sjögren's syndrome. Extensive thymic clonal deletion of CD4(+) T cells occurred in H-2(k/k) double-Tg mice presenting high levels of the I-E(k)-restricted hLa T cell epitope. In contrast, deletion was less extensive in H-2(k/b) double-Tg mice presenting lower levels of the epitope, and some surviving thymocytes were positively selected as thymic regulatory T cells (tTreg). These mice remained serologically tolerant to hLa and healthy. H-2(k/b) double-Tg mice deficient of all endogenous Tcra genes, a deficiency known to impair Treg development and function, produced IgG anti-hLa autoantibodies and displayed defective tTreg development. These autoimmune mice had interstitial lung disease characterized by lymphocytic aggregates containing Tg T cells with an activated, effector memory phenotype. Salivary gland infiltrates were notably absent. Thus, expression of nuclear hLa Ag induces thymic clonal deletion and tTreg selection, and lymphocytic infiltration of the lung is a consequence of La-specific CD4(+) T cell autoimmunity.
Keyphrases
- regulatory t cells
- high fat diet induced
- endothelial cells
- dendritic cells
- case report
- mouse model
- interstitial lung disease
- rheumatoid arthritis
- induced pluripotent stem cells
- wild type
- systemic lupus erythematosus
- pluripotent stem cells
- quantum dots
- insulin resistance
- multiple sclerosis
- pulmonary hypertension
- cancer therapy
- metabolic syndrome
- highly efficient
- long non coding rna
- binding protein
- computed tomography
- idiopathic pulmonary fibrosis
- gene expression
- dna methylation
- plant growth