Abstract

Abstract CD4+CD25+Foxp3+ regulatory T cells (Treg) are essential for maintaining immune tolerance and homeostasis. It has been shown that natural Treg can inhibit up-regulation of costimulatory molecules on dendritic cells (DC). However, the mechanism leading to this phenomenon has not been elucidated. Whether inducible Treg (iTreg) also possess this function has not been previously investigated. Here, we demonstrate that iTreg could inhibit LPS-induced DC maturation and mediate down-regulation of CD80 and CD86 on mature DC. This process is CTLA4-dependent as Treg isolated from CTLA4-/- mice did not down-modulate B7 molecules on DC. Furthermore, CTLA4Ig, but not CD28Ig, mimicked iTreg action. Down-regulation of CD80/CD86 was not due to endocytosis or protease-dependent shedding, but rather to a reverse signaling through B7. CTLA4Ig treatment decreased CD80 and CD86 transcription, as well as NFκB activity upon LPS stimulation. Interestingly, both CTLA4Ig and co-incubation with iTreg induced a profound STAT3 phosphorylation in DC, whereas no significant effect on the proximal NFκB pathway was observed. Inhibition of STAT3 activation partially abolished CTLA4Ig-induced CD80/CD86 down-modulation suggesting involvement of this molecule in the observed process. Our data reveal a novel signaling pathway by which Treg can suppress DC via reverse signaling, and may provide new opportunities for therapies targeting costimulatory pathways.

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