Journal
CELL REPORTS
Volume 30, Issue 4, Pages 1039-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.12.081
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Funding
- NIH [R01-AI119140-03, R03-144-AAH5568, R01 CA203689, P30 CA047904]
- University of Wisconsin Carbone Cancer Center [P30 CA014520]
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Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12 alpha chain (p35) subunits, yet the forms that IL-35 assume and its role in peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in Treg(Eb)(i)(3WT) C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3(TdTom) gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogenspecific Foxp(3)(+) and Foxp3(neg) (iTr35) T cells. Further-more, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance.
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