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A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate
Open accessAbstract
Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (T FH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers 2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hi CD4+ helper T cell population distinct from T FH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand 3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
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“In the blood of patients with SLE, concomitant oxidation of mtDNA and signalling through the Notch pathway induce the expansion of a unique population of CD4+ T cells (CXCR5−CXCR3+PD1hiCD4+ T cells, known as T helper 10 (TH10) cells)75,76”
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“Accumulation of succinate in TH10 cells enables an altered type of electron transport chain activity, ultimately leading to the production of IL-10 and mtROS, and acquisition of B cell helper functions75”
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“These cells might contribute to SLE pathogenesis and end organ damage via supporting extrafollicular humoral responses75”
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“Moreover, pDCs activated by oxidized mtDNA induce a unique population of CD4+ T cells, TH10 (CXCR5−CXCR3+PD1hiCD4+ T cell), that have altered metabolic features; these cells have accumulated levels of mtROS and succinate and produce large amounts of IL-10 and IFNγ but not IL-21 (REF.75).”
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Metadata
- Authors
- Caielli, S., Veiga, D. T., Balasubramanian, P., Athale, S., Domic, B., Murat, E., Banchereau, R., Xu, Z., Chandra, M., Chung, C.-H., Walters, L., Baisch, J., Wright, T., Punaro, M., Nassi, L., Stewart, K., Fuller, J., Ucar, D., Ueno, H., Zhou, J., Banchereau, J., & Pascual, V.
- Affiliations
- Weill Cornell Medicine (US)
- The Jackson Laboratory for Genomic Medicine (US)
- Texas Scottish Rite Hospital for Children (US)
- Icahn School of Medicine at Mount Sinai (US)
- Pathologist Bio-Medical Laboratories (US)
- Corresponding author
- Pascual, Virginia
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-11-26
- Volume
- 25
- Issue
- 1
- Pages
- 75-81
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6325012
- OpenAlex
- W2900950647
- Cited by
- 263
- References
- 51
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 44 · 2023: 32 · 2022: 46 · 2021: 38 · 2020: 35 · 2019: 28 · 2018: 2
- FWCI
- 22.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (U19AI082715)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50AR054083, P50AR070594)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- systemic lupus erythematosus, lupus nephritis, CD4+ T cells, B cell help, IL-10, succinic acid, reverse electron transfer, mitochondrial reactive oxygen species, PD-1, T follicular helper cells, plasmacytoid dendritic cells, oxidized mitochondrial DNA, TLR9, autoantibody production
- MeSH terms
- B-Lymphocytes, Dendritic Cells, DNA, Mitochondrial, Humans, Immunologic Memory, Lupus Erythematosus, Systemic, Lupus Nephritis, Oxidation-Reduction, CD4-Positive T-Lymphocytes, Interleukin-10, Succinic Acid, Cell Proliferation
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