Abstract: TH-PO0684
Synthetic Agonist Peptides Mobilize CD8+ Regulatory T Cells and Ameliorate Systemic Lupus Erythematosus
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Xia, Xi, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Choi, John Yongjoon, Harvard Medical School Department of Medicine, Boston, Massachusetts, United States
- Cantor, Harvey, Dana Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, United States
- Azzi, Jamil R., Harvard Medical School Department of Medicine, Boston, Massachusetts, United States
Background
Our team's previous study using B6.Qa-1-D227K knock-in mice, which harbor a point mutation in Qa-1 that disrupts the interaction between peptide–Qa-1 (pQa-1) complexes and the T cell receptor (TCR) of CD8+regulatory T cells (Tregs), demonstrated the development of systemic lupus erythematosus (SLE)-like disease. These findings underscore the critical role of Qa-1–restricted CD8+ Tregs in lupus pathogenesis. However, the precise functions and underlying mechanisms of this regulatory pathway in SLE remain poorly understood.
Methods
To investigate the role of Qa-1–restricted Ly49+CD8+Tregs in lupus, we utilized both wild-type and B6.Qa-1-D227K knock-in mice in an imiquimod-induced SLE model. CD8+Tregs were depleted using an anti-Ly49F IgG2 antibody to assess their impact on disease progression. Additionally, T cell receptors (TCRs) expressed by Qa-1–restricted CD8+ Tregs were identified, enabling the design of synthetic FL9 self-peptide variants, including a potent analog, FL9-68, used to selectively activate and expand this regulatory population. These interventions were evaluated for their effects on autoantibody production, germinal center (GC) responses, CD4+T follicular helper (Tfh) cell activity, and kidney injury in the imiquimod-induced SLE mouse model.
Results
B6.Qa-1-D227K knock-in mice exhibited accelerated disease progression, elevated autoantibody levels, enhanced GC and Tfh responses, and more severe renal damage compared to wild-type controls. Similarly, depletion of CD8+ Tregs using anti-Ly49F IgG2 antibody exacerbated autoimmunity and kidney pathology. In contrast, treatment with FL9-68 effectively expanded CD8+Tregs and significantly suppressed autoantibody levels, GC and Tfh responses, kidney damage and ameliorated disease symptoms compared to vehicle treated mice.
Conclusion
The synthetic agonist peptide FL9-68 efficiently mobilizes CD8+ regulatory T cells and mitigates lupus-like disease in vivo, offering a promising therapeutic approach for the treatment of SLE.