Identification of cellular composition and architectural organization of tuberculous granulomas in cynomolgus macaques

Infection by Mycobacterium tuberculosis (Mtb), the agent of human tuberculosis (TB), induces formation of leukocyte‐rich granulomas that prevent bacterial dissemination. The cellular composition and organization of granulomas may have important implications on individual's ability to contain Mtb, yet these factors have not been exhaustively examined. To better understand granuloma architecture, we used laser‐scanning confocal microscopy to visualize granulomas from Mtb ‐infected cynomolgus macaques, a primate model of human TB. Granulomas were classified into two broad categories: solid cellular granulomas entirely composed of cells and caseous granulomas with centers composed of acellular necrotic material. Granuloma morphology was organized into three regions: a periphery of normal tissue abutting the granuloma, a ring‐like transition zone between the periphery and center, and a central region of caseum or cells depending on the granuloma type. Cell types within each region were consistent between examined granulomas, with lymphocytes macrophages predominating. Cells including B cells and NK cells were also observed. Numerous cells, including CD3+ lymphocytes, were observed to express TNF‐□ and IFN‐□ in the transition zone. The granuloma periphery included IL‐10 expressing CD3+ lymphocytes and CD68+ macrophages. These results suggest a variety of cell‐types are present in predictable places within granulomas and region‐specific cytokine expression may enhance anti‐Mtb responses in the granuloma and downregulate immune responses outside the granuloma.