Microbial diols, polyols, and phosphate-containing metabolites

Microbial diols, polyols, and phosphate-containing metabolites refers to a diverse set of small-molecule antigens derived from microbial metabolic pathways that are recognized by the human immune system through specialized non-polymorphic molecules (Kjer-Nielsen et al., 2012, Nature). This category primarily includes riboflavin (vitamin B2) biosynthesis intermediates, such as the polyol 5-OP-RU, which are presented by MHC-related protein 1 (MR1) to activate Mucosal-Associated Invariant T (MAIT) cells (Corbett et al., 2014, Nature). Additionally, it encompasses phosphate-containing metabolites known as phosphoantigens, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which are sensed by the intracellular domain of Butyrophilin 3A1 (BTN3A1) to trigger the activation of Vγ9Vδ2 T cells (Vantourout et al., 2013, Cancer Research). These metabolites serve as molecular signatures of infection and metabolic stress, allowing unconventional T cells to rapidly respond to pathogens and malignant cells. While these metabolites are ligands rather than therapeutic targets themselves, the pathways they activate are being exploited for immunotherapy. For instance, aminobisphosphonates like zoledronic acid are used to increase endogenous phosphoantigen levels to stimulate anti-tumor gamma-delta T cell activity, and synthetic analogs are being developed as potent vaccine adjuvants or direct T-cell activators (Rigau et al., 2020, Immunity).

Other names

Microbial metabolitesPhosphoantigensMR1 ligandsBTN3A1 ligandsRiboflavin-derived metabolitesUnconventional T-cell antigens

Activation of unconventional T cells through stabilization of MR1 or BTN3A1; Inhibition of the mevalonate pathway to increase endogenous phosphoantigen levels.