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

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 (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 centers². Here, we describe a CXCR5^-CXCR3⁺ programmed death 1 (PD1)^hiCD4⁺ 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 ligand³. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.