Smith-specific regulatory T cells halt the progression of lupus nephritis

• Published in: Nature communications Vol. 15; no. 1; p. 899
• Main Authors: Eggenhuizen, Peter J., Cheong, Rachel M. Y., Lo, Cecilia, Chang, Janet, Ng, Boaz H., Ting, Yi Tian, Monk, Julie A., Loh, Khai L., Broury, Ashraf, Tay, Elean S. V., Shen, Chanjuan, Zhong, Yong, Lim, Steven, Chung, Jia Xi, Kandane-Rathnayake, Rangi, Koelmeyer, Rachel, Hoi, Alberta, Chaudhry, Ashutosh, Manzanillo, Paolo, Snelgrove, Sarah L., Morand, Eric F., Ooi, Joshua D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-02-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/51; 14/10; 14/34; 14/35; 38/22; 38/77; 38/91; 42/44; 631/250/1619/554/1898/1271; 631/250/2520; 631/250/38; 692/308/2778; Affinity; Animal models; Antigens; Autoimmune diseases; Cell therapy; Chronic conditions; Epitopes; Haplotypes; Histocompatibility antigen HLA; Humanities and Social Sciences; Immune system; Immunological tolerance; Immunoregulation; Inflammation; Lupus; Lupus nephritis; Lymphocytes; Lymphocytes T; multidisciplinary; Nephritis; Science; Science (multidisciplinary); Systemic lupus erythematosus; T cell receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45056-x

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.
Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.