A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization

The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection. [Display omitted] •Diverse cell populations and inflammatory cues characterize tuberculous granulomas•Granuloma macrophages that express E-cadherin display type 2 immune signatures•stat6 functions cell autonomously in granuloma macrophage epithelioid transformation•A type 2/Stat6 axis coordinates necrotic granuloma formation and epithelialization During mycobacterial infections, a non-canonical type 2 immune response underlies the formation and epithelial architecture of the granuloma, the hallmark structure of tuberculosis.