INTERFERON λ-TREATED DENDRITIC CELLS SPECIFICALLY INDUCE PROLIFERATION OF FOXP3-EXPRESSING SUPPRESSOR T CELLS Short title: IFNλ generates tolerogenic DCs

The interferons λ (IFNsλ), also known as IL-28 and IL-29, are co-expressed with IFNβ following Toll Like Receptor (TLR) stimulation in human monocyte-derived dendritic cells (DCs). IFNλ shares with type I IFNs an intracellular signaling pathway which drives the expression of a common set of gene. However, IFNλ signaling is initiated through a membrane receptor system distinct from that of type I IFNs. Because IFNs produced by DCs in response to TLR stimulation are critical in both differentiation and maturation of DCs, we sought to investigate whether IFNλ exhibits specific effects on DCs differentiation. We show in this work that DCs acquire IFNλ responsiveness through the expression of the specific IFNλ receptor chain during their differentiation from monocytes. IFNλ-treated DCs express high levels of MHC I and II but low levels of costimulatory molecules. However, they express CCR7 and acquire the ability to migrate to lymph nodes when intravenously injected into SCID/Bg mice. In MLR cultures, IFNλ-treated DCs specifically induced an IL-2dependent proliferation of a CD4, CD25, Foxp3 T cell subset with contact-dependent suppressive activity on T cells proliferation initiated by fully mature DCs. IFNλ are thus able to generate tolerogenic DCs, an activity that could thwart IFNβ functions. For personal use only. on November 12, 2017. by guest www.bloodjournal.org From