ICOS/B7h Bidirectional Signal to Induce Secretion of IL-1β and IL-17 (46.3)

Abstract B7h is constitutively expressed by antigen presenting cells (APC) and binds ICOS expressed by activated T cells. ICOS triggering costimulates T helper (TH) cell activation and modulates their cytokine secretion, whereas the effect of B7h triggering in APC is unknown. This work investigated B7h reverse signalling in dendritic cells (DC). We induced DC maturation with LPS in the presence or absence of a soluble ICOS-Ig fusion protein; then, both cytokine secretion and allostimolatory activity were evaluated. B7h stimulation substantially modulated LPS-induced DC maturation by influencing cytokine secretion. The most striking effect was 80-fold increase of IL-1b secretion, but other changes were 3-fold increase of IL-10 and 2-fold decrease of TNF-a. In IL-1b secretion, B7h triggering acted as a "second signal" by activating caspase-1, required to cleave pro-IL-1b whose synthesis was induced by LPS. B7h triggering on LPS-activated DC also modulated their capacity to activate allogeneic T cells in mixed lymphocyte cultures (MLC) by decreasing the proliferative response and changing cytokines secretion, including 20-fold decrease of IFN-g and 5-fold increase of IL-17. This effect was partly ascribable to the cytokine milieu secreted by DC and particularly to the high IL-1b levels, known to be involved in differetiation of human Th17 cells. However, ICOS triggering too played a role in IL-17 secretion since blocking of the B7h/ICOS interaction inhibited IL-17 secretion in MLC with DC. Moreover, in naive Th cells activated with anti-CD3 antibodies, ICOS stimulation induced IL-17 secretion in the presence of exogenous IL-1b. In this work we showed that B7h-mediated reverse signaling induced IL-1b by DCs which in turn favors IL-17 secretion by Th cells. On the other side, we demonstrated that ICOS costimulation directly favors Th17 differentiation.