CaltechAUTHORS
  A Caltech Library Service

Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood

McCaffrey, Erin F. and Donato, Michele and Keren, Leeat and Chen, Zhenghao and Fitzpatrick, Megan and Jojic, Vladimir and Delmastro, Alea and Greenwald, Noah F. and Baranski, Alex and Graf, William and Bosse, Marc and Ramdial, Pratista K. and Forgo, Erna and Van Valen, David and van de Rijn, Matt and Bendall, Sean C. and Banaei, Niaz and Steyn, Adrie J. C. and Khatri, Purvesh and Angelo, Michael (2020) Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200610-093054353

[img] PDF - Submitted Version
Creative Commons Attribution Non-commercial No Derivatives.

37Mb
[img] PDF (Extended Data Figures) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

10Mb
[img] PDF (Extended Data Table 1) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

33Kb
[img] PDF (Extended Data Table 2) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

56Kb
[img] PDF (Extended Data Table 3) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

24Kb
[img] PDF (Extended Data Table 4) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

63Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20200610-093054353

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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.06.08.140426DOIDiscussion Paper
ORCID:
AuthorORCID
McCaffrey, Erin F.0000-0001-7241-1798
Keren, Leeat0000-0002-6799-6303
Van Valen, David0000-0001-7534-7621
Bendall, Sean C.0000-0003-1341-2453
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.
Funders:
Funding AgencyGrant Number
NSF Graduate Research Fellowship2017242837
Damon Runyon Cancer Research FoundationDRG-2292-17
European Molecular Biology Organization (EMBO)ALTF 1128-2016
NIHF31CA246880
NIHR61/33AI138280
NIHR01AI134810
CRDF GlobalUNSPECIFIED
Medical Research Council (South Africa)UNSPECIFIED
National Research Foundation (South Africa)UNSPECIFIED
NIH1-DP5-OD019822
NIH1R01AG056287
NIH1R01AG057915
NIH1U24CA224309
Bill and Melinda Gates FoundationUNSPECIFIED
Stanford Cancer InstituteUNSPECIFIED
NIHU19 AI104209
NIHR01 AR067145
NIHR01 AI32494
Record Number:CaltechAUTHORS:20200610-093054353
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200610-093054353
Official Citation:Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood. Erin F. McCaffrey, Michele Donato, Leeat Keren, Zhenghao Chen, Megan Fitzpatrick, Vladimir Jojic, Alea Delmastro, Noah F. Greenwald, Alex Baranski, William Graf, Marc Bosse, Pratista K. Ramdial, Erna Forgo, David Van Valen, Matt van de Rijn, Sean C. Bendall, Niaz Banaei, Adrie J.C. Steyn, Purvesh Khatri, Michael Angelo. bioRxiv 2020.06.08.140426; doi: https://doi.org/10.1101/2020.06.08.140426
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103815
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Jun 2020 16:47
Last Modified:10 Jun 2020 16:47

Repository Staff Only: item control page