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

Peter J. Eggenhuizen, Rachel M. Y. Cheong, Cecilia Lo, Janet Chang, Boaz H. Ng, Yi Tian Ting, Julie A. Monk, Khai L. Loh, Ashraf Broury, Elean S. V. Tay, Chanjuan Shen, Yong Zhong, Steven Lim, Jia Xi Chung, Rangi Kandane-Rathnayake, Rachel Koelmeyer, Alberta Hoi, Ashutosh Chaudhry, Paolo Manzanillo, Sarah L. Snelgrove, Eric F. Morand and Joshua D. Ooi ()
Additional contact information
Peter J. Eggenhuizen: Monash University
Rachel M. Y. Cheong: Monash University
Cecilia Lo: Monash University
Janet Chang: Monash University
Boaz H. Ng: Monash University
Yi Tian Ting: Monash University
Julie A. Monk: Monash University
Khai L. Loh: Monash University
Ashraf Broury: Monash University
Elean S. V. Tay: Monash University
Chanjuan Shen: Central South University
Yong Zhong: Monash University
Steven Lim: Alfred Research Alliance Flow Cytometry Core Facility
Jia Xi Chung: Monash University
Rangi Kandane-Rathnayake: Monash University
Rachel Koelmeyer: Monash University
Alberta Hoi: Monash University
Ashutosh Chaudhry: Former Employee of Amgen
Paolo Manzanillo: Amgen Inc
Sarah L. Snelgrove: Monash University
Eric F. Morand: Monash University
Joshua D. Ooi: Monash University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45056-x

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