Nucleosome-Specific Regulatory T Cells Engineered by Triple Gene Transfer Suppress a Systemic Autoimmune Disease

Abstract

The mechanisms of systemic autoimmune disease are poorly understood and available therapies often lead to immunosuppressive conditions. We describe here a new model of autoantigen-specific immunotherapy based on the sites of autoantigen presentation in systemic autoimmune disease. Nucleosomes are one of the well-characterized autoantigens. We found relative splenic localization of the stimulative capacity for nucleosome-specific T cells in (NZB × NZW)F1 (NZB/W F1) lupus-prone mice. Splenic dendritic cells (DCs) from NZB/W F1 mice spontaneously stimulate nucleosome-specific T cells to a much greater degree than both DCs from normal mice and DCs from the lymph nodes of NZB/W F1 mice. This leads to a strategy for the local delivery of therapeutic molecules using autoantigen-specific T cells. Nucleosome-specific regulatory T cells engineered by triple gene transfer (TCR-α, TCR-β, and CTLA4Ig) accumulated in the spleen and suppressed the related pathogenic autoantibody production. Nephritis was drastically suppressed without impairing the T cell-dependent humoral immune responses. Thus, autoantigen-specific regulatory T cells engineered by multiple gene transfer is a promising strategy for treating autoimmune diseases.

CD4+CD25−LAG3+regulatory T cells controlled by the transcription factor Egr-2

“…The experimental groups consisted of CD4 ϩ T cells from BALB/c or DO11.10 mice transduced with pMIG or pMIG-Egr2. In accordance with our previous experiments (30,31), the average transduction efficiency was Ϸ50%. The GFP-positive fraction of the transduced CD4 ϩ T cells were sorted with FACSAria and transferred to immunized mice.…”

“…To examine the in vivo suppressive activity of Egr-2, we next performed the delayed-type hypersensitivity (DTH) reaction of BALB/c mice against chicken ovalbumin (OVA) by using T cells transduced with the Egr2 gene. The in vivo functions of T cells transduced with regulatory genes have been verified (30,31). In this experiment, CD4 ϩ T cells from BALB/c mice were transduced with pMIG or pMIG-Egr2.…”

IL-17B and IL-17C Are Associated with TNF-α Production and Contribute to the Exacerbation of Inflammatory Arthritis

“…Retroviral gene transduction was performed, as described previously (30,31). A CD4 ϩ T cell population was prepared by negative selection by MACS with anti-CD19 mAb, anti-CD11c mAb, and anti-CD8a mAb (BD Pharmingen).…”

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

“…Plat-E (25) packaging cells were transfected with a retrovirus vector using the FuGENE 6 transfection reagent (Roche), and retroviral supernatants were harvested at 48 h after the transfection. Retroviral gene transduction was performed as described previously (24,26). Total splenocytes were cultured for 48 h in the presence of Con A (10 mg/ml) and recombinant murine IL-2 (50 ng/ml).…”