The immunoregulatory landscape of human tuberculosis granulomas

• Type of Material: Article
• Authors: Erin F McCaffrey, Stanford University; Michele Donato, Stanford University; Leeat Keren, Weizmann Institute of Science; Zhenghao Chen, Calico Life Sciences LLC; Alea Delmastro, Stanford University; Megan B Fitzpatrick, University of Wisconsin, Madison; Sanjana Gupta, Stanford University; Noah F Greenwald, Stanford University; Alex Baranski, Stanford University; William Graf, California Institute of Technology; Rashmi Kumar, Stanford University; Marc Bosse, Stanford University; Christine Camacho Fullaway, Stanford University; Pratista K Ramdial, University of Kwazulu Natal; Erna Forgó, Stanford University; Vladimir Jojic, Calico Life Sciences LLC; David Van Valen, California Institute of Technology; Smriti Mehra, Texas Biomedical Research Institute; Shabaana A Khader, Washington University; Sean C Bendall, Stanford University; Matt van de Rijn, Stanford University; Daniel Kalman, Emory University; Deepak Kaushal, Texas Biomedical Research Institute; Robert L Hunter, University of Texas Health Sciences Center at Houston; Niaz Banaei, Stanford University; Adrie JC Steyn, University of Kwazulu Natal; Purvesh Khatri, Stanford University; Michael Angelo, Stanford University
• Language: English
• Date: 2022-01-20
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022, corrected publication 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-021-01121-x
• Title of Journal or Parent Work: NATURE IMMUNOLOGY
• Volume: 23
• Issue: 2
• Start Page: 318
• End Page: +
• Keywords: BLOOD; EXPANSION; IMPAIRS; INFLAMMATION; MECHANISMS; Life Sciences & Biomedicine; DISSEMINATION; Science & Technology; TUMOR; Immunology; REGULATORY T-CELLS; MICROENVIRONMENT; SARCOIDOSIS

Abstract

Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-β, regulatory T cells and IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of peripheral blood from patients with TB, immunoregulatory trends mirror those identified by granuloma imaging. Notably, PD-L1 expression is associated with progression to active TB and treatment response. These data indicate that in TB granulomas, there are local spatially coordinated immunoregulatory programs with systemic manifestations that define active TB.