Type III IFNs (IFNλs) expressed in tuberculosis (TB) granulomas enhance anti-mycobacterial activity of macrophages

Abstract

Abstract Granulomas are the pathologic hallmark of Mycobacterium tuberculosis (Mtb) infection. How a granuloma functions at limiting Mtb growth depends on the qualitative balance of pro- and anti-inflammatory cytokines in these lesions. Understanding which cytokines constitute protective and detrimental inflammation in TB is important for the improvement of current TB therapeutics. The type III interferon (IFN) family is composed of four isoforms and includes IL-29, IL-28A, IL-28B, and IFNλ4. These cytokines may be important regulators of inflammation in TB, yet little is known about their relation with TB or whether they have different properties in granulomas than type I IFN (IFNα/β), which is associated with severe TB. We identified that IFNλ is expressed at a significantly higher level in TB granulomas than non-disease lung, and negatively correlates with the CFU/granuloma. IHC characterization of IFNλ expression in granulomas revealed neutrophils and macrophages expressing IFNλ1 and IFNλ4, with neutrophils having a higher percentage of IFNλ expression. IFNλ1 and IFNλ4 differed in their intracellular localization, IFNλ4 having a significantly higher nuclear localization in macrophages than IFNλ1. IFNλ1 treatment of monocyte-derived macrophages induced the expression of different proinflammatory genes at the transcript level and costimulatory molecules like CD86 at the protein level. Further, pretreatment of macrophages with IFNλ1 inhibited the transcriptional activity in a reporter Mtb strain and follow-up experiments suggested this was accompanied by increased acidification of macrophage lysosomes. Our findings suggest that IFNλs may have unappreciated roles in regulating inflammation at the site of disease in TB. Supported by Grant from NIH entitled Pitt HIV-TB Research and Training Program in India (grant number: D43 TW010039)