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

• Published in: Nature medicine Vol. 25; no. 1; pp. 75 - 81
• Main Authors: Caielli, Simone, Veiga, Diogo Troggian, Balasubramanian, Preetha, Athale, Shruti, Domic, Bojana, Murat, Elise, Banchereau, Romain, Xu, Zhaohui, Chandra, Manjari, Chung, Cheng-Han, Walters, Lynnette, Baisch, Jeanine, Wright, Tracey, Punaro, Marilynn, Nassi, Lorien, Stewart, Katie, Fuller, Julie, Ucar, Duygu, Ueno, Hideki, Zhou, Joseph, Banchereau, Jacques, Pascual, Virginia
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2019; Nature Publishing Group
• Subjects: 631/250/249/1313/1613/1614; 631/250/38; Apoptosis; Autoantibodies; Autoimmune diseases; B-Lymphocytes - immunology; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Chronic conditions; CXCR3 protein; CXCR5 protein; Cytokines; Dendritic cells; Dendritic Cells - metabolism; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; Electron transport; Humans; Immunologic Memory; Infectious Diseases; Interleukin 10; Interleukin 21; Interleukin-10 - metabolism; Letter; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lupus nephritis; Lupus Nephritis - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Metabolic Diseases; Mitochondrial DNA; Molecular Medicine; Nephritis; Neurosciences; Oxidation-Reduction; Pathogenesis; PD-1 protein; Priming; Reactive oxygen species; Succinic Acid - metabolism; Systemic lupus erythematosus; Target recognition; Therapeutic applications; Toll-like receptors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0254-9

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 centers 2 . Here, we describe a CXCR5 − CXCR3 + programmed death 1 (PD1) hi CD4 + 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 ligand 3 . Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE. A new population of T helper cells employs unique signals to support autoreactive B cells in patients with systemic lupus erythematosus.