Type 1 interferon expression and signaling occur in distinct regions in granulomas during Mycobacterium tuberculosis infection

Abstract

Abstract Type 1 interferon (IFN1s) expression is associated with progression of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb). This relationship has been assessed in murine models of TB and in human peripheral blood and airway cells, but IFN1 expression in human granulomas, the lesions associated with TB, and disease has not been addressed. To determine if IFN1s are expressed in granulomas, which cells express them, and which cells undergo IFN1-regulated signaling, we investigated these factors in granulomas from macaques, an animal model that recapitulates human TB. We found that IFN1s and interferon stimulated genes (ISGs) were expressed at higher levels in granulomas than uninfected lung. In granulomas, the strongest expression was observed within epithelioid macrophages, a subset of cells that are in close proximity to Mtb, but other myeloid cells including some neutrophils and alveolar macrophages also expressed IFN1s. The lymphocyte cuff showed greater expression of the IFN1 receptor, IFNAR1, and also expressed more of the ISG MX1 than the epithelioid macrophage region. These data indicate that IFN1 is expressed by epithelioid macrophages and IFN1-related signaling occurs within the lymphocyte cuff. These results suggest that IFN1 expression may be due to the presence of Mtb or Mtb antigens and that IFN1-regulated signaling and responses are spatially distinct from the regions and cells where IFN1 expression occurs.