Unraveling the immunological ecosystem of human tuberculosis
Abstract/Contents
- Abstract
- Outcomes in tuberculosis (TB) infection are thought to be driven in part by underlying differences in the phenotype and structure of cells in granulomas, the histological hallmark of TB. However, high-dimensional phenotypic and spatial analysis of TB granulomas has not been conducted. Here, we utilize multiplexed ion beam imaging by time of flight (MIBI-TOF) to construct a map of the composition and architecture of human TB granulomas. MIBI-TOF employs mass spectrometry to image metal-conjugated antibodies, allowing multiplexed single-cell phenotyping that retains the spatial organization of complex tissues. We applied MIBI-TOF to a cohort of clinical specimens from patients with TB disease, revealing the complex single cell composition of granulomas, including a spectrum of myeloid subsets and a highly ordered structure of protein expression. We then used a spatial adaptation of the machine learning algorithm, Latent Dirichlet Allocation (spatial-LDA), to identify cellular microenvironments indicative of spatially coordinated immune responses in TB. This revealed an immunosuppressed microenvironment with spatially coordinated co-expression of IDO1 and PD-L1 by myeloid cells, proliferating regulatory T cells, and high levels of TGFB along with a near absence of IFNg and markers consistent with T-cell activation, supporting a myeloid-mediated mechanism of immune suppression. We observed similar trends in gene expression of an immunoregulatory program in a confirmatory transcriptomic analysis of peripheral blood collected from over 1500 individuals with TB infection and healthy controls across 29 cohorts spanning 14 countries. Overall, this first-of-its-kind systems analysis of human granulomas raises the possibility of myeloid-mediated immune suppression within the granuloma and 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.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | McCaffrey, Erin Francis |
|---|---|
| Degree supervisor | D'Angelo, Robert |
| Thesis advisor | D'Angelo, Robert |
| Thesis advisor | Banaei, Niaz |
| Thesis advisor | Bendall, Sean, 1979- |
| Thesis advisor | Davis, Mark M |
| Degree committee member | Banaei, Niaz |
| Degree committee member | Bendall, Sean, 1979- |
| Degree committee member | Davis, Mark M |
| Associated with | Stanford University, Department of Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Erin Francis McCaffrey. |
|---|---|
| Note | Submitted to the Department of Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/hb092sm4955 |
Access conditions
- Copyright
- © 2022 by Erin Francis McCaffrey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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