The immunoregulatory landscape of human tuberculosis granulomas
- Creators
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McCaffrey, Erin F.
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Donato, Michele
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Keren, Leeat
- Chen, Zhenghao
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Delmastro, Alea
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Fitzpatrick, Megan B.
- Gupta, Sanjana
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Greenwald, Noah F.
- Baranski, Alex
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Graf, William
- Kumar, Rashmi
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Bosse, Marc
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Camacho Fullaway, Christine
- Ramdial, Pratista K.
- Forgó, Erna
- Jojic, Vladimir
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Van Valen, David
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Mehra, Smriti
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Khader, Shabaana A.
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Bendall, Sean C.
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van de Rijn, Matt
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Kalman, Daniel
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Kaushal, Deepak
- Hunter, Robert L.
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Banaei, Niaz
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Steyn, Adrie J. C.
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Khatri, Purvesh
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Angelo, Michael
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.
Additional Information
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 25 May 2021; Accepted 14 December 2021; Published 20 January 2022. We thank T. Risom, D. Glass, M. Carter, J. Mattila, J. Flynn and A. Kasmar for discussions and comments. We thank P. Chu and the Stanford Human Histology Core for providing technical assistance. E.F.M. was supported by the National Science Foundation (graduate research fellowship grant 2017242837) and training grant 5T32AI007290. L.K. was a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2292-17) and a nonstipendiary awardee of the EMBO long-term fellowship (ALTF 1128–2016). N.F.G. was supported by the National Cancer Institute (grant CA246880-01) and Stanford University (graduate fellowship). A.J.C.S. was supported by the National Institutes of Health (grants R61/33AI138280 and R01AI134810), CRDF Global, the South African Medical Research Council and a National Research Foundation BRICS multilateral grant. P.K. was funded in part by the Bill and Melinda Gates Foundation (OPP1113682), the National Institute of Allergy and Infectious Diseases (grants 1U19AI109662, U19AI057229 and 5R01AI125197), the Department of Defense (contracts W81XWH-18-1-0253 and W81XWH1910235) and the Ralph & Marian Falk Medical Research Trust. M.A. was supported by the National Institutes of Health (grants 5U54CA20997105, 5DP5OD01982205, 1R01CA24063801A1, 5R01AG06827902, 5UH3CA24663303, 5R01CA22952904, 1U24CA22430901, 5R01AG05791504 and 5R01AG05628705), the Department of Defense (contracts W81XWH2110143), the Wellcome Trust and other funding from the Bill and Melinda Gates Foundation, Cancer Research Institute, the Parker Center for Cancer Immunotherapy and the Breast Cancer Research Foundation. Data availability: All images and annotated single-cell data are deposited in Mendeley's data repository and can be accessed using the following link: https://doi.org/10.17632/dr5fkgtrb6. Code availability: All custom code used to analyze data has been deposited in GitHub and can be accessed using the following link: https://github.com/angelolab/publications/2022-McCaffrey_etal_HumanTB. Author Contributions: E.F.M. conceived the study design, performed experiments, analyzed data, and wrote the manuscript. M.D. and S.G. conducted the blood transcriptomics analysis. L.K. assisted with analysis conceptualization. Z.C. and V.J. implemented the spatial-LDA analysis. L.K., A.D., N.F.G., A.B. and W.G. assisted with data analysis. R.K. assisted with ISH analysis. A.D., M.B. and C.C. assisted with assay development. D.V.V. developed DeepCell. D. Kalman, D. Kaushal, S.A.K. and S.M. assisted with study and analysis conceptualization. M.F., P.K.R., E.F., M.V.D.R., N.B., R.L.H. and A.J.C.S. provided human samples and consulted on tissue cohort design. S.C.B., P.K. and M.A. supervised the work. Competing interests: M.A. and S.C.B. are inventors on patent US20150287578A1, which covers the mass spectrometry approach utilized by MIBI-TOF to detect elemental reporters in tissue using secondary ion mass spectrometry. M.A. and S.C.B. are board members and shareholders in IonPath, which develops and manufactures the commercial MIBI-TOF platform. E.F.M. has previously consulted for IonPath. The remaining authors declare no competing interests. Peer review information: Nature Immunology thanks Joel Ernst and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. N. Bernard was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.Errata
McCaffrey, E.F., Donato, M., Keren, L. et al. Author Correction: The immunoregulatory landscape of human tuberculosis granulomas. Nat Immunol (2022). https://doi.org/10.1038/s41590-022-01178-2Attached Files
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Erratum - s41590-022-01178-2.pdf
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Additional details
- PMCID
- PMC8810384
- Eprint ID
- 113124
- Resolver ID
- CaltechAUTHORS:20220126-630616000
- NSF Graduate Research Fellowship
- 2017242837
- NIH Predoctoral Fellowship
- 5T32AI007290
- Damon Runyon Cancer Research Foundation
- DRG-2292-17
- European Molecular Biology Organization (EMBO)
- ALTF 1128-2016
- NIH
- CA246880-01
- Stanford University
- NIH
- R61/33AI138280
- NIH
- R01AI134810
- CRDF Global
- Medical Research Council (South Africa)
- National Research Foundation (South Africa)
- Bill and Melinda Gates Foundation
- OPP1113682
- NIH
- 1U19AI109662
- NIH
- U19AI057229
- NIH
- 5R01AI125197
- Department of Defense
- W81XWH-18-1-0253
- Department of Defense
- W81XWH1910235
- Ralph and Marian Falk Medical Research Trust
- NIH
- 5U54CA20997105
- NIH
- 5DP5OD01982205
- NIH
- 1R01CA24063801A1
- NIH
- 5R01AG06827902
- NIH
- 5UH3CA24663303
- NIH
- 5R01CA22952904
- NIH
- 1U24CA22430901
- NIH
- 5R01AG05791504
- NIH
- 5R01AG05628705
- Department of Defense
- W81XWH2110143
- Wellcome Trust
- Cancer Research Institute
- Parker Institute for Cancer Immunotherapy
- Breast Cancer Research Foundation
- Created
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2022-01-28Created from EPrint's datestamp field
- Updated
-
2022-07-28Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering (BBE)