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Published June 10, 2020 | Supplemental Material + Submitted
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Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that is distinctly characterized by granuloma formation within infected tissues. Granulomas are dynamic and organized immune cell aggregates that limit dissemination, but can also hinder bacterial clearance. Consequently, outcome in TB is influenced by how granuloma structure and composition shift the balance between these two functions. To date, our understanding of what factors drive granuloma function in humans is limited. With this in mind, we used Multiplexed Ion Beam Imaging by Time-of-Flight (MIBI-TOF) to profile 37 proteins in tissues from thirteen patients with active TB disease from the U.S. and South Africa. With this dataset, we constructed a comprehensive tissue atlas where the lineage, functional state, and spatial distribution of 19 unique cell subsets were mapped onto eight phenotypically-distinct granuloma microenvironments. This work revealed an immunosuppressed microenvironment specific to TB granulomas with spatially coordinated co-expression of IDO1 and PD-L1 by myeloid cells and proliferating regulatory T cells. Interestingly, this microenvironment lacked markers consistent with T-cell activation, supporting a myeloid-mediated mechanism of immune suppression. We observed similar trends in gene expression of immunoregulatory proteins in a confirmatory transcriptomic analysis of peripheral blood collected from over 1500 individuals with latent or active TB infection and healthy controls across 29 cohorts spanning 14 countries. Notably, PD-L1 gene expression was found to correlate with TB progression and treatment response, supporting its potential use as a blood-based biomarker. Taken together, this study serves as a framework for leveraging independent cohorts and complementary methodologies to understand how local and systemic immune responses are linked in human health and disease.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Posted June 09, 2020. The authors thank Tyler Risom, David Glass, Matthew Carter, and Anne Kasmar for discussions and comments. The authors thank Pauline Chu and the Stanford Human Histology Core for providing technical assistance. E.F.M was supported by the NSF Graduate Research Fellowship (grant no. 2017242837). L.K. was a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2292-17) and a non-stipendiary awardee of the EMBO Long-Term fellowship (ALTF 1128–2016). Noah Greenwald was supported by F31CA246880. A.J.C.S. was supported R61/33AI138280, R01AI134810, the CRDF Global, the South African Medical Research Council, and an NRF BRICS Multilateral grant to A.J.C.S. M.A. was supported by 1-DP5-OD019822. S.C.B. and M.A. were jointly supported by 1R01AG056287 and 1R01AG057915, 1U24CA224309, the Bill and Melinda Gates Foundation, and a Translational Research Award from the Stanford Cancer Institute. S.J.G. was supported by U19 AI104209, R01 AR067145, and R01 AI32494.

Attached Files

Submitted - 2020.06.08.140426v1.full.pdf

Supplemental Material - media-1.pdf

Supplemental Material - media-2.pdf

Supplemental Material - media-3.pdf

Supplemental Material - media-4.pdf

Supplemental Material - media-5.pdf

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Additional details

Created:
August 19, 2023
Modified:
December 13, 2023