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

S Caielli, DT Veiga, P Balasubramanian, S Athale… - Nature medicine, 2019 - nature.com
S Caielli, DT Veiga, P Balasubramanian, S Athale, B Domic, E Murat, R Banchereau, Z Xu…
Nature medicine, 2019nature.com
Understanding the mechanisms underlying autoantibody development will accelerate
therapeutic target identification in autoimmune diseases such as systemic lupus
erythematosus (SLE). 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 centers. Here, we
describe a CXCR5− CXCR3+ programmed death 1 (PD1) hiCD4+ helper T cell population …
Abstract
Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE). 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 centers. 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 ligand. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
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