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; Joshua D. Ooi

doi:10.1038/s41467-024-45056-x

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. SnelgroveEric F. Morand, Joshua D. Ooi

Research output: Contribution to journal › Article › Research › peer-review

36 Citations (Scopus)

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.

Original language	English
Article number	899
Number of pages	14
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45056-x
Publication status	Published - 6 Feb 2024

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SDG 3 Good Health and Well-being

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Eggenhuizen, P. J., Cheong, R. M. Y., Lo, C., Chang, J., Ng, B. H., Ting, Y. T., Monk, J. A., Loh, K. L., Broury, A., Tay, E. S. V., Shen, C., Zhong, Y., Lim, S., Chung, J. X., Kandane-Rathnayake, R., Koelmeyer, R., Hoi, A., Chaudhry, A., Manzanillo, P., ... Ooi, J. D. (2024). Smith-specific regulatory T cells halt the progression of lupus nephritis. Nature Communications, 15(1), Article 899. https://doi.org/10.1038/s41467-024-45056-x

@article{5ee6a0e1ea2d4c41a20fe10d9ab2a328,

title = "Smith-specific regulatory T cells halt the progression of lupus nephritis",

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.",

author = "Eggenhuizen, \{Peter J.\} and Cheong, \{Rachel M.Y.\} and Cecilia Lo and Janet Chang and Ng, \{Boaz H.\} and Ting, \{Yi Tian\} and Monk, \{Julie A.\} and Loh, \{Khai L.\} and Ashraf Broury and Tay, \{Elean S.V.\} and Chanjuan Shen and Yong Zhong and Steven Lim and Chung, \{Jia Xi\} and Rangi Kandane-Rathnayake and Rachel Koelmeyer and Alberta Hoi and Ashutosh Chaudhry and Paolo Manzanillo and Snelgrove, \{Sarah L.\} and Morand, \{Eric F.\} and Ooi, \{Joshua D.\}",

note = "Funding Information: The authors declare the following competing interests: Relevant funding was awarded by Lupus Research Alliance Inc., Funder ID 100012051, 588087, and 850279 (J.D.O.), National Health and Medical Research Council (NHMRC), Funder ID 501100000925, 2017877 (J.D.O.), Amgen Inc., Funder ID 100002429, 2021026213-001 (J.D.O.), United States Department of Defense, Funder id 100000005, LR210065 (J.D.O.). The research has been partially supported by Amgen. PCT patent application (PCT/AU2021/050254) has been filed by Monash University as the sole applicant. Inventors: J.D.O., P.J.E., and E.F.M. The remaining authors declare no competing interests. Funding Information: The authors wish to thank all donors for their blood donations: Angela Vais from the Monash Histology Platform for histology work, Michael Thomson from the Monash Health Translation Precinct (MHTP) Flow Core Facility for flow cytometry sorting, the staff at Micromon Genomics for single-cell sequencing and staff at MHTP Animal Facilities for mouse colony care and management. Relevant funding was awarded by Lupus Research Alliance Inc., Funder ID 100012051, 588087 and 850279 (J.D.O.), National Health and Medical Research Council (NHMRC), Funder ID 501100000925, 2017877 (J.D.O.), Amgen Inc., Funder ID 100002429, 2021026213-001 (J.D.O.), United States Department of Defense, Funder ID 100000005, LR210065 (J.D.O.). Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

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doi = "10.1038/s41467-024-45056-x",

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Eggenhuizen, PJ, Cheong, RMY, Lo, C, Chang, J, Ng, BH, Ting, YT, Monk, JA, Loh, KL, Broury, A, Tay, ESV, Shen, C, Zhong, Y, Lim, S, Chung, JX, Kandane-Rathnayake, R , Koelmeyer, R , Hoi, A, Chaudhry, A, Manzanillo, P, Snelgrove, SL, Morand, EF & Ooi, JD 2024, 'Smith-specific regulatory T cells halt the progression of lupus nephritis', Nature Communications, vol. 15, no. 1, 899. https://doi.org/10.1038/s41467-024-45056-x

TY - JOUR

T1 - Smith-specific regulatory T cells halt the progression of lupus nephritis

AU - Eggenhuizen, Peter J.

AU - Cheong, Rachel M.Y.

AU - Lo, Cecilia

AU - Chang, Janet

AU - Ng, Boaz H.

AU - Ting, Yi Tian

AU - Monk, Julie A.

AU - Loh, Khai L.

AU - Broury, Ashraf

AU - Tay, Elean S.V.

AU - Shen, Chanjuan

AU - Zhong, Yong

AU - Lim, Steven

AU - Chung, Jia Xi

AU - Kandane-Rathnayake, Rangi

AU - Koelmeyer, Rachel

AU - Hoi, Alberta

AU - Chaudhry, Ashutosh

AU - Manzanillo, Paolo

AU - Snelgrove, Sarah L.

AU - Morand, Eric F.

AU - Ooi, Joshua D.

N1 - Funding Information: The authors declare the following competing interests: Relevant funding was awarded by Lupus Research Alliance Inc., Funder ID 100012051, 588087, and 850279 (J.D.O.), National Health and Medical Research Council (NHMRC), Funder ID 501100000925, 2017877 (J.D.O.), Amgen Inc., Funder ID 100002429, 2021026213-001 (J.D.O.), United States Department of Defense, Funder id 100000005, LR210065 (J.D.O.). The research has been partially supported by Amgen. PCT patent application (PCT/AU2021/050254) has been filed by Monash University as the sole applicant. Inventors: J.D.O., P.J.E., and E.F.M. The remaining authors declare no competing interests. Funding Information: The authors wish to thank all donors for their blood donations: Angela Vais from the Monash Histology Platform for histology work, Michael Thomson from the Monash Health Translation Precinct (MHTP) Flow Core Facility for flow cytometry sorting, the staff at Micromon Genomics for single-cell sequencing and staff at MHTP Animal Facilities for mouse colony care and management. Relevant funding was awarded by Lupus Research Alliance Inc., Funder ID 100012051, 588087 and 850279 (J.D.O.), National Health and Medical Research Council (NHMRC), Funder ID 501100000925, 2017877 (J.D.O.), Amgen Inc., Funder ID 100002429, 2021026213-001 (J.D.O.), United States Department of Defense, Funder ID 100000005, LR210065 (J.D.O.). Publisher Copyright: © The Author(s) 2024.

PY - 2024/2/6

Y1 - 2024/2/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85184218842

U2 - 10.1038/s41467-024-45056-x

DO - 10.1038/s41467-024-45056-x

M3 - Article

C2 - 38321013

AN - SCOPUS:85184218842

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 899

ER -

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

Abstract

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Targeted Regulatory T Cells to Treat SLE

FlowCore (FLOW)

Monash Genomics & Bioinformatics Platform (MGBP)

Monash Histology Platform (MHP)

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

Abstract

UN SDGs

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Targeted Regulatory T Cells to Treat SLE

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FlowCore (FLOW)

Monash Genomics & Bioinformatics Platform (MGBP)

Monash Histology Platform (MHP)

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