IFN-α Suppresses Myeloid Cytokine Production, Impairing IL-12 Production and the Ability to Support T cell Proliferation.

IFN-α can suppress production of T cell polarizing cytokines or induce inhibitory antigen presenting cells that suppress T cell activation. Previous studies showed that IFN-α therapy fails to boost virus-specific T cell immunity in patients with chronic Hepatitis B virus (HBV) infection. Our aim was to determine whether IFN-α exposure alters human antigen presenting cell function in vivo. We investigated the immunomodulatory effects using healthy donor PBMC exposed to IFN-α, and chronic hepatitis B (CHB) patients starting IFN-α therapy. IFN-α increased HLA-DR, CD80, CD86 and PD-L1 expression on healthy donor monocytes. In contrast to the activated phenotype, IFN-α inhibited TLR-induced cytokine production and monocyte-induced T cell proliferation. In CHB patients, peg-IFN treatment induced an interferon-stimulated gene signature in monocytes and increased HLA-DR, CD80, CD86 and PD-L1 expression. As early as 3d after CHB patients started treatment, IFN-α inhibited monocyte cytokine production and T cell stimulation ex vivo. IFN-α-mediated inhibition of IL-12 production, rather than inhibitory receptor expression, was responsible for inhibition of T cell proliferation. Addition of IL-12 restored T cell proliferation to baseline levels. Understanding how professional antigen presenting cells respond to immunomodulation is important for both new innate and adaptive-targeted immunotherapies.