The immunoregulatory landscape of human tuberculosis granulomas

Vladimir Jojic

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.