CaltechAUTHORS
Published February 2022 | Version Erratum + Published + Supplemental Material
Journal Article Open

The immunoregulatory landscape of human tuberculosis granulomas

Creators

  • 1. ROR icon Stanford University
  • 2. ROR icon Weizmann Institute of Science
  • 3. ROR icon University of Wisconsin–Madison
  • 4. ROR icon California Institute of Technology
  • 5. ROR icon University of KwaZulu-Natal
  • 6. ROR icon Texas Biomedical Research Institute
  • 7. ROR icon Washington University in St. Louis
  • 8. ROR icon Emory University
  • 9. ROR icon The University of Texas Health Science Center at Houston
  • 10. ROR icon University of Alabama at Birmingham

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/s41590-022-01178-2

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Additional details

Identifiers

PMCID
PMC8810384
Eprint ID
113124
Resolver ID
CaltechAUTHORS:20220126-630616000

Related works

Describes
10.17632/dr5fkgtrb6 (DOI)
https://github.com/angelolab/publications/2022-McCaffrey_etal_HumanTB (URL)
10.1038/s41590-022-01178-2 (DOI)

Funding

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

Dates

Created
2022-01-28
Created from EPrint's datestamp field
Updated
2022-07-28
Created from EPrint's last_modified field

Caltech Custom Metadata

Caltech groups
Division of Biology and Biological Engineering (BBE)