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

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


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.