Differential control of Helios+/-Treg development by monocyte subsets through disparate inflammatory cytokines

Abstract

Foxp31 regulatory T cells (Tregs) play a pivotal role in control of autoimmunity and pathological immune responses. Helios, the Ikarus family transcription factor, binds to the Foxp3 promoter, stabilizing its expression, and is expressed in 70% of peripheral Tregs of healthy individuals. This frequency is altered during malignancy, infection, and autoimmunity, although the mechanisms that control proliferation and relative numbers of Helios+/- Tregs remain largely unknown. Using a T-cell-monocyte in vitro stimulation assay, we now show that proliferation of Helios1 Tregs is inhibited by CD161 monocyte subset. Antibody blocking with anti-interleukin (IL)-12 reversed this inhibition, whereas addition of IL-12 suppressed Helios1 Treg expansion, indicating that CD161 monocyte control of Helios1 Treg numbers is mediated through IL-12. In contrast, proliferation of Helios2 Tregs, which express higher levels of tumor necrosis factor receptor II (TNFRII), was suppressed by TNF-a, whereas anti-TNF-a and anti-TNFRII reversed the inhibition. CD162 monocyte subset was mainly responsible for TNF-a-mediated control of Helios2 Treg expansion. Altogether, these data suggest a differential role for monocyte subsets in control of Helios+/- Treg development that is mediated by distinct inflammatory cytokines. These data may have important implications for understanding the pathogenesis as well as control of chronic inflammatory and autoimmune diseases.