Differential control of Helios(+/-) Treg development by monocyte subsets through disparate inflammatory cytokines.
Foxp3(+) 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 Helios(+) Tregs is inhibited by CD16(+) monocyte subset. Antibody blocking with anti-interleukin (IL)-12 reversed this inhibition, whereas addition of IL-12 suppressed Helios(+) Treg expansion, indicating that CD16(+) monocyte control of Helios(+) Treg numbers is mediated through IL-12. In contrast, proliferation of Helios(-) Tregs, which express higher levels of tumor necrosis factor receptor II (TNFRII), was suppressed by TNF-α, whereas anti-TNF-α and anti-TNFRII reversed the inhibition. CD16(-) monocyte subset was mainly responsible for TNF-α-mediated control of Helios(-) 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.
Laboratory of Complement Biology, New York Blood Center, New York, NY 10065, USA.
Hui
H
Zhong
Karina
K
Yazdanbakhsh
D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D038041:Lymphopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D017452:Receptors, IgG / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D016207:Cytokines; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C111431:IKZF2 protein, human; D018836:Inflammation Mediators; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D051740:Ikaros Transcription Factor; D018664:Interleukin-12