Type III interferons are expressed in tuberculous granulomas and promote inflammatory phenotypes in macrophages that differ from type I interferons
Humans and non-human primates express four subtypes of type 3 interferons (IFNλs; IFNλ1-IFNλ4). Unlike type I interferons, which have been thoroughly investigated in tuberculosis (TB), the role of IFNλs and their effects on immunity in TB remain unknown. We examined IFNλ1 and IFNλ4 expression in cynomolgus macaques with TB and investigated the effects of IFNα/β, IFNλ1, and IFNλ4 signaling on macaque macrophages. Using IHC, we identified differential expression of IFNλ1 and IFNλ4 in granuloma macrophages and neutrophils, including IFNλ4 localization in the nuclei of epithelioid and alveolar macrophages. Further, we found that macrophages and neutrophils from chronic TB granulomas express more IFNλ1 than those from acute infections. To measure IFNλ1 and IFNλ4’s effect on macrophage gene expression and compare these cytokines against IFNα/β, we used NanoString transcriptional profiling and Ingenuity Pathway Analysis (IPA) on cytokine-stimulated macrophages to identify differentially regulated pathways. We found that IFNα/β upregulated the greatest number of genes, followed by IFNλ1, and these two cytokines induced different genes and pathways, whereas IFNλ4 stimulation had minimal effect on gene expression. We used a live/dead reporter Mtb strain to determine how IFNλ1 and IFNλ4 affect macrophage antimycobacterial activity and found that IFNλ1 pretreatment inhibited bacterial fluorescent reporter expression suggesting this cytokine promotes antimycobacterial activity. Taken together, these data suggest that IFNλs have non-redundant properties with type 1 interferons that may promote macrophage activation, inflammation, and antibacterial activity in TB.