Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6 <sup>+</sup> B helper T cells in systemic lupus erythematosus
Federica Facciotti, Paola Larghi, Roberto Bosotti, Chiara Vasco, Nicola Gagliani, Chiara Cordiglieri, Saveria Mazzara, Valeria Ranzani, Elsa Rottoli, Serena Maria Curti, Alessandra Penatti, B. Karnani, Yasushi Kobayashi, Mariacristina Crosti, Mauro Bombaci, Jan Piet van Hamburg, Grazisa Rossetti, Roberta Gualtierotti, Maria Gerosa, Stefano Gatti, Sara Torretta, Lorenzo Pignataro, Sander W. Tas, Sergio Abrignani, Massimiliano Pagani, Fabio Grassi, Pier Luigi Meroni, Richard A. Flavell, Jens Geginat
Abstract
Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4 + CCR6 + IL-7R + T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6 + B helper T cells were phenotypically distinct from follicular helper T (T FH ) cells and lacked BCL6 expression. In peripheral blood, a CCR6 + T cell population with similar characteristics was identified, which lacked Th17- and T FH -associated gene signatures and differentiation-associated surface markers. CD4 + CCR6 + T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4 + CCR6 + IL-7R + T cells were associated with the presence of pathogenic anti-dsDNA (double-stranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10–producing CCR6 + T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.