Rnf20 inhibition enhances immunotherapy by improving regulatory T cell generation

Abstract

Background: Allergic disorders are common all over the world. The pathogenesis of allergy is unclear. Therapies for allergic disorders require improvement. Endoplasmic reticulum (ER) stress is one of the factors influencing immune response. The purpose of this study is to improve the effectiveness of immunotherapy for experimental respiratory allergy by targeting the ER stress signal pathway.

Methods: Committed CD4⁺ T cells were isolated from blood samples collected from patients with allergic rhinitis (AR) and TCR ovalbumin transgenic mice. The effects of TCR engagement and 3-methyl-4-nitrophenol (MNP) on inducing ER stress in committed CD4⁺ T cells were evaluated.

Results: ER stress was detected in antigen-specific CD4⁺ T cells (sCD4⁺ T cells) of AR patients. The environmental pollutant MNP increased the expression of the X-binding protein-1 (XBP1) in the committed CD4⁺ T cells during the TCR engagement. XBP1 mediated the effects of MNP on inhibiting regulatory T cell (Treg) generation. The effects of MNP on induction of protein 20 (Rnf20) in CD4⁺ T cells were mediated by XBP1. Inhibition of Rnf20 rescued the Treg development from MNP-primed sCD4⁺ T cells. The ablation of Rnf20 improved the immunotherapy of AR through the restoration of the Treg generation.

Conclusions: ER stress can be detected in CD4⁺ T cells in TCR engagement. Exposure to MNP exacerbates ER stress in committed CD4⁺ T cells. Regulation of the ER stress-related Rnf20 expression can restore the generation of Treg from CD4⁺ T cells of subjects with allergic diseases.

Keywords: Allergy; CD4 T cell; Endoplasmic reticulum stress; Environmental pollutant; Immune regulatory cell.