TY - JOUR
T1 - A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate
AU - Caielli, Simone
AU - Veiga, Diogo Troggian
AU - Balasubramanian, Preetha
AU - Athale, Shruti
AU - Domic, Bojana
AU - Murat, Elise
AU - Banchereau, Romain
AU - Xu, Zhaohui
AU - Chandra, Manjari
AU - Chung, Cheng Han
AU - Walters, Lynnette
AU - Baisch, Jeanine
AU - Wright, Tracey
AU - Punaro, Marilynn
AU - Nassi, Lorien
AU - Stewart, Katie
AU - Fuller, Julie
AU - Ucar, Duygu
AU - Ueno, Hideki
AU - Zhou, Joseph
AU - Banchereau, Jacques
AU - Pascual, Virginia
N1 - Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85057454532
U2 - 10.1038/s41591-018-0254-9
DO - 10.1038/s41591-018-0254-9
M3 - Article
C2 - 30478422
AN - SCOPUS:85057454532
SN - 1078-8956
VL - 25
SP - 75
EP - 81
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -