Interplay between CD45RA+ regulatory T cells and TNF-α in the regulation of human Th17 differentiation

Abstract

The balance between effector CD4+ T cells secreting IL-17 (Th17) and regulatory T cells (Treg) plays an important role in autoimmune disorders that include rheumatoid arthritis (RA) and Crohn's disease. Tumor necrosis factor (TNF)-α is a key pro-inflammatory cytokine that contributes to disease pathogenesis. We investigated the interplay between CD45RA+ Treg and TNF-α in the regulation of human Th17 differentiation. We found that CD45RA+ Treg promoted while TNF-α inhibited naive CD4+ T-cell differentiation into IL-17 and CCL20 co-expressing Th17 cells without influencing their IL-22 release. Unexpectedly, CD45RA1 Treg depletion abrogated TNF-α suppressive function. Finally, dendritic cell-derived TNF-α suppressed the development of IL-17+CCL20+ expressing Th17 cells. In conclusion, CD45RA+ Treg positively governs human Th17 development, which is impaired by TNF-α. We propose that TNF-α may represent a negative feedback mechanism to control IL-17/CCL20but not IL-22-associated autoimmune pathologies. © The Japanese Society for Immunology. 2010. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.