Internal medicine

CXCR5

Systemic lupus erythematosus

Disease

Population

Biology

Interleukin 21

Cytotoxic T cell

Antibody

Autoantibody

In vitro

Immunology

T cell

B cell

Lupus nephritis

CD40

Germinal center

Biochemistry

Medicine

Immune system

Environmental health

Nature Medicine

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. A new population of T helper cells employs unique signals to support autoreactive B cells in patients with systemic lupus erythematosus.

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