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

Abstract

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-2k/k double transgenic mice presenting high levels of the I-Ek-restricted hLa T cell epitope. In contrast, deletion was less extensive in H-2k/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-2k/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.

Tissue resident memory T cells in the human conjunctiva and immune signatures in human dry eye disease

“…T lymphocytes have been described in the human and rodent conjunctiva13, and ocular surface T cells play a critical pathogenic role in DED, the commonest clinical manifestation of ocular surface inflammation222324252627282930. Here, we have used impression cytology and flow cytometry to characterize recirculating (naïve, T CM , T EM , T EMRA , T RCM ) and non-recirculating (T RM ) T cell subsets (Figs 1A and 2A) in the healthy human ocular surface and in patients with DED.…”

“…In experimental rodent DED, T cells are implicated in disease pathogenesis and adoptive transfer of pathogenic T cells is sufficient to impart DED in naïve recipients2324252627323637. Although the T-cell immunosuppressant cyclosporine A is a cornerstone of DED therapy, the direct involvement of T cells in human DED is harder to demonstrate.…”

“…The disease can be induced in animal models by the transfer of pathogenic T cells25. Animals with defects in regulatory T cells exhibit more severe DED2627. The importance of T cells in human DED is underscored by the efficacy of cyclosporine, a T cell immunosuppressant that is a cornerstone of DED therapy282930.…”

Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3+ regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B

“…H‐2 k/k .Thy1.1 +/+ congenic mice to generate heterozygous hLa transgenic (hLa Tg) or non‐Tg H‐2 k/k Thy1.1 +/+ and H‐2 k/b Thy1.1 +/+ recipient mice. 3B5.8 + hLa‐specific TCR Tg mice described previously were crossed to Tcra –/– (B6.129S2‐ Tcra tm1Mom /J; Jackson Laboratory) and B6.H‐2 k congenic mice to generate B6. 3B5.8 +/– .Tcra –/– .H‐2 k/k and B6.…”

“…Using mice expressing transgenic (Tg) human La (hLa) with ubiquitous, nuclear distribution at physiological levels, we have previously reported detectable immunological tolerance in hLa‐specific CD4 + T cells, but not in B lymphocytes . Further studies revealed that human La‐specific T cells in double Tg mice for an I‐E k ‐restricted T cell receptor (TCR) specific for hLa 67–76 peptide and the hLa neo‐self‐antigen undergo drastic but incomplete thymic clonal deletion . A portion of residual, hLa‐specific thymocytes in these mice developed into natural thymic regulatory T cells (T reg ), and the mice displayed high proportions of forkhead box P3 (FoxP3)‐expressing, hLa‐specific CD4 + T cells in peripheral lymphoid organs that functioned to maintain immunological self‐tolerance and prevent autoimmune lung pathology.…”