Targeting regulatory T cells in chronic inflammatory disease. (MPF2P.749)

Abstract

Abstract Human regulatory T cells (Tregs) are functionally characterized by their ability to suppress effector T cells in addition to having an essential role in maintaining immunological tolerance. Activated Tregs are upregulated in chronic inflammation and studies in human tuberculosis (TB) patients indicate that patients with active disease have increased frequency of Tregs in peripheral blood compared to patients with latent TB. Tregs also play a role in chronic viral infections. In HIV, Tregs control viral replication in early stages of the disease but limit immune activation and pathogen specific immune responses in later stages. The MAPK/ERK signaling pathway has been shown to be involved in the regulation of the FoxP3 transcription factor, the major regulator of Treg suppressive function. We aimed to target activation of disease specific Tregs by inhibition of the MEK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Upon stimulation of patient PBMCs with TB- and HIV-specific antigens in presence of MEK inhibitors, we observed significantly downregulated levels of FoxP3 in resting Tregs (CD45RA+FoxP3+) and a reduced number of activated Tregs (CD45RA-FoxP3++). Differential effects on production of IFNγ TNFα and IL-2 could be observed. In conclusion, MEK inhibitors modulate disease antigen-specific Treg activation which may have potential application in new treatment approaches where limiting Treg activity would be favourable.