Chung Edmund Y M, Wang Yuan Min, Shaw Karli, Ronning Emily, Wang Ya, Zhang Geoff Yu, Hu Min, Keung Karen, McCarthy Hugh J, Harris David C H, Stephen Alexander
Centre for Kidney Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
Nephrology (Carlton). 2025 Feb;30(2):e70005. doi: 10.1111/nep.70005.
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.
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.
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).
Peptide vaccination induces CD8 Tregs that ameliorate induction of experimental membranous nephropathy which may represent a further peripheral regulation of autoimmunity.
CD8调节性T细胞（Tregs）在多种自身免疫性动物模型中具有交叉保护作用。最近，有报道称，来自酵母肽-主要组织相容性复合体文库的特定肽可在小鼠实验性多发性硬化症中扩增CD8 Tregs。这些肽是否也能扩增CD8 Tregs并预防膜性肾病的实验模型——海曼肾炎（HN）尚不清楚。我们旨在评估肽疫苗接种在HN中诱导CD8 Tregs的疗效。
用Fx1A/完全弗氏佐剂免疫Lewis大鼠以诱导HN，并在疾病诱导前1周（预防接种）或诱导后1周（治疗接种）接受肽疫苗接种。为了解肽疫苗接种的效果是否由CD8 Tregs介导，我们在肽疫苗接种1周后将CD8 T细胞过继转移到HN大鼠体内。
预防接种而非治疗接种显著降低了抗Fx1A自身抗体水平和血清肌酐。预防接种和治疗接种均减轻了肾脏组织学损伤。主要CD8 Treg转录因子Helios的mRNA表达在预防接种后的脾脏和肾脏以及治疗接种后的肾脏中均上调。肽疫苗接种后过继转移CD8 T细胞可显著降低血清肌酐、蛋白尿、肾脏组织学损伤、抗Fx1A自身抗体水平、生发中心形成以及T滤泡辅助细胞（Bcl6、白细胞介素-21）、辅助性T细胞1（干扰素-γ、Tbet）和辅助性T细胞17（白细胞介素-6、白细胞介素-17）标志物的mRNA表达。
肽疫苗接种可诱导CD8 Tregs，减轻实验性膜性肾病的诱导，这可能代表了自身免疫的进一步外周调节。
