Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

The costimulatory CD40L–CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII+ B cells, dendritic cells and macrophages in human MS lesions. Here we investigated the role of the CD40 downstream signaling intermediates TNF receptor‐associated factor 2 (TRAF2) and TRAF6 in MHCII+ cells in experimental autoimmune encephalomyelitis (EAE). Both MHCII–CD40–Traf2−/− and MHCII–CD40–Traf6−/− mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only MHCII–CD40–Traf6−/− mice displayed a decrease in myeloid and lymphoid cell infiltration into the CNS that was accompanied by reduced levels of TNF‐α, IL‐6 and IFN‐γ. As CD40–TRAF6 interactions predominantly occur in macrophages, we subjected CD40flflLysMcre mice to EAE. This myeloid‐specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination.