CD8+ Regulatory T Cells Induced by Peptide Vaccination Ameliorates Experimental Model of Membranous Nephropathy.

Abstract

Aim: CD8⁺ regulatory T cells (Tregs) are cross-protective across multiple animal models of autoimmunity. Recently, specific peptides from a yeast-peptide-major histocompatibility complex library that expanded CD8⁺ Tregs in murine experimental multiple sclerosis were reported. Whether these peptides also expand CD8⁺ Tregs and protect against Heymann nephritis (HN), an experimental model of membranous nephropathy is unknown. We aimed to assess the efficacy of peptide vaccination to induce CD8⁺ Tregs in HN.

Methods: Lewis rats were immunised with Fx1A/complete Freund's adjuvant to induce HN and received peptide vaccination 1 week before (prevention vaccination) or 1 week after disease induction (treatment vaccination). To understand whether the effect of peptide vaccination was mediated by CD8⁺ Tregs, we adoptively transferred CD8⁺ T cells 1 week after peptide vaccination into HN rats.

Results: Prevention vaccination, but not treatment vaccination, significantly reduced anti-Fx1A autoantibody levels and serum creatinine. Both prevention and treatment vaccination reduced histological kidney injury. mRNA expression of Helios, the major CD8⁺ Treg transcription factor, was upregulated in both the spleen and kidney with prevention vaccination and in the kidney with treatment vaccination. Adoptive transfer of CD8⁺ T cells after peptide vaccination significantly reduced serum creatinine, proteinuria, histological kidney injury, anti-Fx1A autoantibody levels, germinal centre formation, and mRNA expression of markers of T follicular helper cells (Bcl6, interleukin-21), T helper 1 cells (interferon-γ, Tbet) and T helper 17 cells (interleukin-6, interleukin-17).

Conclusions: Peptide vaccination induces CD8⁺ Tregs that ameliorate induction of experimental membranous nephropathy which may represent a further peripheral regulation of autoimmunity.