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

摘要

The balance between effector CD4+ T cells secreting IL-17 (T_h17) 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 T_h17 differentiation. We found that CD45RA+ Treg promoted while TNF-α inhibited naive CD4+ T-cell differentiation into IL-17 and CCL20 co-expressing T_h17 cells without influencing their IL-22 release. Unexpectedly, CD45RA+ Treg depletion abrogated TNF-α suppressive function. Finally, dendritic cell-derived TNF-α suppressed the development of IL-17+CCL20+ expressing T_h17 cells. In conclusion, CD45RA+ Treg positively governs human T_h17 development, which is impaired by TNF-α. We propose that TNF-α may represent a negative feedback mechanism to control IL-17/CCL20- but not IL-22-associated autoimmune pathologies.