Engineered antigen-specific T regulatory cells suppress autoreactivity to the anti-glomerular basement membrane disease antigen

Peter J Eggenhuizen; Boaz H Ng; Cecilia Lo; Janet Chang; Sarah L Snelgrove; Rachel My Cheong; Chanjuan Shen; Steven Lim; Yong Zhong; Poh-Yi Gan; Joshua D Ooi

doi:10.1016/j.kint.2025.01.005

Engineered antigen-specific T regulatory cells suppress autoreactivity to the anti-glomerular basement membrane disease antigen

Kidney Int. 2025 Jan 20:S0085-2538(25)00061-4. doi: 10.1016/j.kint.2025.01.005. Online ahead of print.

Authors

Affiliations

¹ Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia.
² Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia; Dept. of Hematology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, China.
³ Alfred Research Alliance Flow Cytometry Core Facility, Melbourne, Victoria, Australia.
⁴ Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia; Dept. of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
⁵ Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia. Electronic address: joshua.ooi@monash.edu.

PMID: 39842638
DOI: 10.1016/j.kint.2025.01.005

Abstract

Anti-glomerular basement membrane (anti-GBM) disease is accompanied by insufficient antigen-specific T regulatory cells (Tregs) and clonally expanded antigen-specific T conventional cells (Tconvs). In particular, this applied to the immunodominant T cell auto- epitope of type IV collagen, α3(IV)NC1135-145 , presented by HLA-DR15. Here, we investigated whether Tregs engineered to express GBM-T cell receptors (TCR) specific for α3(IV)NC1135- 145 better suppress autoimmunity. The GBM-TCR Treg cell product exhibited a phenotypically stable Treg phenotype, produced a α3(IV)NC1135-145-specific functional responses, and were superior suppressors of autoreactive Tconvs and bystander Tconvs compared to polyclonal Tregs or irrelevant TCR-transduced Tregs. We also found that GBM- TCR Tregs modulate other immune cells like dendritic cells and B cells to a more tolerogenic phenotype. Importantly, our findings support the development of GBM-TCR Tregs as a promising cell-based therapy for anti-GBM disease.

Keywords: Anti-glomerular basement membrane (GBM) disease; Autoimmune disease; Cell therapy; Glomerulonephritis (GN); T cell receptor (TCR); T regulatory cell (Treg).