A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

Simone Caielli, Diogo Troggian Veiga, Preetha Balasubramanian, Shruti Athale, Bojana Domic, Elise Murat, Romain Banchereau, Zhaohui Xu, Manjari Chandra, Cheng Han Chung, Lynnette Walters, Jeanine Baisch, Tracey Wright, Marilynn Punaro, Lorien A Nassi, Katie Stewart, Julie Fuller, Duygu Ucar, Hideki Ueno, Joseph ZhouJacques Banchereau, Virginia Pascual

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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 (TFH 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 centers2. Here, we describe a CXCR5CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH 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 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

Original languageEnglish (US)
Pages (from-to)75-81
Number of pages7
JournalNature medicine
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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. A., Stewart, K., Fuller, J., Ucar, D., Ueno, H., ... Pascual, V. (2019). A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nature medicine, 25(1), 75-81. https://doi.org/10.1038/s41591-018-0254-9