Defective selection of thymic regulatory T cells accompanies autoimmunity and pulmonary infiltrates in Tcra-deficient mice double transgenic for human La/SS-B and human La-specific T cell receptor

摘要

A human La/SS-B (hLa)-specific TCR/hLa neo-self antigen double transgenic mouse model was developed and used to investigate cellular tolerance and autoimmunity to the ubiquitous RNA-binding La antigen 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 transgenic 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 transgenic 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 transgenic 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 transgenic T cells with an activated, effector memory phenotype. Salivary gland infiltrates were notably absent. Thus, expression of nuclear hLa antigen induces thymic clonal deletion and tTreg selection, and lymphocytic infiltration of the lung is a consequence of La-specific CD4⁺ T cell autoimmunity.