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

Nat Med. 2019 Jan;25(1):75-81. doi: 10.1038/s41591-018-0254-9. Epub 2018 Nov 26.

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 CXCR5-CXCR3+ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • DNA, Mitochondrial / genetics
  • Dendritic Cells / metabolism
  • Humans
  • Immunologic Memory
  • Interleukin-10 / metabolism*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Nephritis / immunology
  • Oxidation-Reduction
  • Succinic Acid / metabolism*

Substances

  • DNA, Mitochondrial
  • Interleukin-10
  • Succinic Acid