The immunoregulatory landscape of human tuberculosis granulomas

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.

Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications

“…As these patients are advanced TB cases with cavitary TB, who underwent lung resection surgery, the results may not be generalised to the whole spectrum of TB disease, which constitutes a limitation to the study. Nevertheless, our study included a larger number of samples in comparison to previous approaches and there are few papers published working on TB lung lesion, in total using 79 samples from 24 patients 13,16,17 . To our knowledge, this is the first study that has built and validated a transcriptional signature of a human TB granuloma from fresh TB lesion biopsy samples, using different granuloma compartments and including, not also MDR/XDR-TB patients as Dheda et al 11 , but also, DS-TB patients.…”

Single-cell Spatial Proteomic Imaging for Human Neuropathology

“…We also used this approach to delineate features from individuals with cognitive impairment (Figure S2B). Taken together, much like multiplexed analysis of the immune system and other tissues (Glass et al, 2019; Hartmann and Bendall, 2020; Hartmann et al, 2021; Keren et al, 2018; Liu et al, 2021; McCaffrey et al, 2022; Moore et al, 2021), combinatorial protein expression patterns provided a snapshot of functional organization or proteopathy within brain regions. This low-level analysis of multiplexed proteomic data could serve as a guide for ‘fingerprinting’ human brain and be used to model progression in neurodegeneration.…”

“…Here, we present a new generation of single-cell, spatial proteomic imaging, and analytical tools to capture the underlying cellular and phenotypic diversity in intricate neural tissues. In place of fluorophores and lasers, we employed multiplex ion beam imaging by time of flight (MIBI-TOF) mass spectrometry (MS) that has been used previously to study various archival human tissue types from tumors to placenta and granulomas in infectious disease (Greenbaum et al, 2021; Keren et al, 2018; Liu et al, 2021; McCaffrey et al, 2022; Risom et al, 2022). Based on secondary ion mass spectrometry (SIMS), MIBI-TOF images antigens targeted by antibodies labelled with elemental isotopic mass reporters that are spatially quantified with nanometer resolution.…”

In the Thick of It: Formation of the Tuberculous Granuloma and Its Effects on Host and Therapeutic Responses

“…Interrogation of the local inflammatory environment within granulomas in Mtb infected mice and macaques also found that there was a pronounced TGFβ signature within the granuloma ( 125 ). Similarly, using histological techniques and mass spectrometry, elevated TGFβ signaling and induction of downstream genes have recently been described in human patient samples as well ( 103 ). Using TGFβR-deficient mice, TGFβ was found to act in a T cell intrinsic fashion to repress Th1 differentiation within the granuloma ( 125 ).…”

“…Thus, the inability for T cell responses to completely eliminate Mtb in infected patients appears to be, at least in part, due to the spatial restriction of T cells to sites distant from infected macrophages ( 26 ). Similarly, both NK cells and CD8 T cells are known to be recruited to granulomas in humans and animal models of Mtb infection ( 15 , 103 , 104 ). CD8 cells, have been found to be crucial to control of Mtb burden in the mouse model in vivo ( 105 , 106 ).…”