Type III interferons are expressed in tuberculosis granulomas and may influence signaling in epithelioid macrophages

Abstract Granulomas are the pathologic hallmark of Mycobacterium tuberculosis (Mtb) infection. Balanced pro- and anti-inflammatory cytokines regulate inflammation in tuberculosis (TB) and determine outcomes at the lesional and organismal level. Understanding what constitutes protective and detrimental inflammation in TB is important for the improvement of current TB therapeutics. The type III interferon family is composed of four isoforms and includes IL-29, IL-28A, IL-28B, and the recently classified IFNλ4. These cytokines may be important regulators of inflammation in TB yet little is known about their relationship with TB or whether they have different properties in granulomas than type I interferons (IFNα/β), a family of cytokines associated with severe TB. To better understand the relationship between IFNλ, IFNα, and TB we characterized IFNλ expression in formalin-fixed paraffin-embedded granulomas from cynomolgus macaques and investigated cytokine expression and STAT phosphorylation by macaque peripheral blood, lung, and lymph node cells. We found that IL-29 and IL-28B are expressed by epithelioid macrophages and neutrophils in granulomas and IFNλ4 had a unique expression in the transcriptionally active region of epithelioid macrophage nuclei suggesting a possible regulatory role for IFNλ4 in these cells. Experiments were also performed to compare IFNα and IFNλ’s effect on antimycobacterial responses in monocyte-derived macrophages, and ability to induce STAT phosphorylation and pro- and anti-inflammatory cytokine expression by T cells, macrophages, monocytes, and neutrophils. Our findings suggest that IFNλ may have unappreciated roles in regulating inflammation at the site of disease in TB.