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

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.