Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation, autoantibody production, and immune complex deposition
We have demonstrated that synthetic peptides based on T cell determinants in the VH region of IgG which encode murine antibodies to DNA that bind to MHC Class I/II regions can activate CD8+ T cells in vitro, which can result in the suppression of co-cultured CD4+ T helper cells and B cell activities [26, 27]
We found that pCons treatment increased the cell surface expression of CD25 and CD122 in CD4+ T cells compared to naïve CD4+ T cells (Figure 1A Panels A, C, E, H, J, L)
Summary
SLE is an autoimmune disease characterized by widespread inflammation, autoantibody production, and immune complex deposition. Investigating the genes, regulatory networks, and signaling pathways that regulate the functional activity and survival of CD8+ Treg cells is important for development of therapies for restoring immune homeostasis in SLE and other autoimmune diseases. We have developed a unique model in which CD8+ regulatory T cells can be induced to suppress the development of autoimmune disease in an animal model of lupus, the (NZB/NZW) F1 (BWF1) mouse [3, 5, 25, 26] In this model, we have demonstrated that synthetic peptides (pCons) based on T cell determinants in the VH region of IgG which encode murine antibodies to DNA that bind to MHC Class I/II regions can activate CD8+ T cells in vitro, which can result in the suppression of co-cultured CD4+ T helper cells and B cell activities [26, 27]. We showed that pCons induces CD8+FoxP3+ Treg cells in healthy human peripheral blood mononuclear cells (PBMCs)
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