Single-cell immune profiling at time of M. tuberculosis exposure reveals antigen-reactive programs that predict progression to active disease
This article has been Reviewed by the following groups
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- Evaluated articles (Rapid Reviews Infectious Diseases)
Abstract
Early delineation of host immune responses at the moment of Mycobacterium tuberculosis (Mtb) exposure and infection is critical to identify individuals at risk of progressing to active tuberculosis (TB). We performed single-cell transcriptional profiling of over 500,000 peripheral blood mononuclear cells from 57 HIV-negative close contacts of TB cases in Brazil, including 25 individuals who developed active disease within two years (progressors) and 32 matched controls who remained disease-free (non-progressors). Cells were stimulated separately with the MTB300 peptide pool or irradiated Mtb (gRV), enabling resolution of antigen-reactive states across adaptive (CD4⁺ T-cells expressing abundant cytokines including IFNG, TNF, and IL17F) and trained-innate lineages, such as NK cells (producing GM-CSF, IFNG, CCL3, CCL4) and monocytes (GM-CSF, IL12B, IL36G). Progressors exhibited early hyper-metabolic CD4⁺ T-cell programs and proliferative NK cell signatures, whereas non-progressors preferentially upregulated complement activation and CCL3/4-driven chemokine signaling in monocytes. Notably, among progressors, gene expression profiles within antigen-reactive CD4⁺ T-cells and monocytes predicted the timing of progression to active TB. Together, these findings reveal high frequencies and functional diversity of antigen-reactive cells in Mtb-exposed individuals and nominate tractable immune correlates for the rational design of next-generation TB vaccines.
Article activity feed
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Benjamin Bimber
Review 4: "Single-cell Immune Profiling at Time of M. Tuberculosis Exposure Reveals Antigen-Reactive Programs that Predict Progression to Active Disease"
Reviewers cautioned on using the term "Mtb-reactive" compared to "Mtb-associated" without providing additional evidence or a nuanced discussion on whether a specific cell state truly recognizes Mtb or is a bystander to another population interacting with it.
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Shoshana Zha
Review 3: "Single-cell Immune Profiling at Time of M. Tuberculosis Exposure Reveals Antigen-Reactive Programs that Predict Progression to Active Disease"
Reviewers cautioned on using the term "Mtb-reactive" compared to "Mtb-associated" without providing additional evidence or a nuanced discussion on whether a specific cell state truly recognizes Mtb or is a bystander to another population interacting with it.
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Nicholas Borcherding
Review 2: "Single-cell Immune Profiling at Time of M. Tuberculosis Exposure Reveals Antigen-Reactive Programs that Predict Progression to Active Disease"
Reviewers cautioned on using the term "Mtb-reactive" compared to "Mtb-associated" without providing additional evidence or a nuanced discussion on whether a specific cell state truly recognizes Mtb or is a bystander to another population interacting with it.
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Megan MacLeod
Review 1: "Single-cell Immune Profiling at Time of M. Tuberculosis Exposure Reveals Antigen-Reactive Programs that Predict Progression to Active Disease"
Reviewers cautioned on using the term "Mtb-reactive" compared to "Mtb-associated" without providing additional evidence or a nuanced discussion on whether a specific cell state truly recognizes Mtb or is a bystander to another population interacting with it.
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Strength of evidence
Reviewer(s): M MacLeod (University of Glasgow) | 📒📒📒 ◻️◻️
N Borcherding (Washington University in St. Louis) | 📒📒📒◻️◻️
Shoshana Z (UCSF) | 📒📒📒◻️◻️
B Bimber (Oregon Health & Science University) | 📒📒📒◻️◻️ -
