Blocking of LFA-1 enhances expansion of Th17 cells induced by human CD14(+) CD16(++) nonclassical monocytes.

Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14(++) CD16(-) (cMo) and intermediate CD14(++) CD16(+) (iMo) Mos are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14(+) CD16(++) Mo (nMo) on T-cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HDs) to activate IL-17(+) T-cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When cocultured with autologous CD4(+) T cells in the absence of TLR-2/NOD2 agonists, PB nMos from HDs were more efficient stimulators of IL-17-producing T cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA-1/ICAM-1 interaction resulted in a significant increase in the percentage of IL-17(+) T cells expanded in nMo/T-cell cocultures. As compared to HD, PB Mo subsets of patients with rheumatoid arthritis were hampered in their T-cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T-cell responses and suggest that nMo could become a critical therapeutic target against IL-17-mediated inflammatory diseases.

Beyond a logic of effectiveness: Horizontal coordination, democratic legitimacy and accountability

Horizontal coordination, where actors join together to accomplish a common task, has been applauded for its output legitimacy. However, such processes often face challenges due to opposition from local actors who raise concerns about democratic legitimacy and accountability. Moving beyond a logic of effectiveness, we aim to show how and why other forms of legitimacy such as input and throughput dimensions also affect horizontal coordination, in addition to output criteria. Beyond the assumed positive relationship between coordination and effectiveness, we additionally expect horizontal coordination to be (a) impeded by local actors' fear of losing democratic legitimacy; and (b) fostered by accountability in terms of the steering capacity of the state. A comparative case study analysis of water supply structures at the regional level in Switzerland shows, in contrast to our expectation, that effectiveness has mixed impacts on horizontal coordination. Rather than being solely a positive factor for horizontal coordination, certain output criteria such as financial redistribution are found to be a key hindrance. We also find that democratic legitimacy may, indeed, impede horizontal coordination whereas increased accountability positively affects such coordination.