Novel Mycobacterial Small Molecules That Bind MR1 And Are Activating Or Antagonistic For MR1-Restricted T cells.

SUMMARY

• TB bacterium, Mycobacterium tuberculosis (M. tuberculosis), is extremely slow growing compared to other bacteria and is naturally resistant to many of the powerful antibiotics that are effective against other bacterial infections. In recent years, multi-drug-resistant TB strains (MDR-TB) have arisen that are resistant to standard treatment and require extensive and costly treatment with new cocktails of potent, toxic drugs.

• Mucosal-associated invariant T cells (MAITs) are a non-classical T cell subset that recognize microbial-derived vitamin B metabolites in the context of major histocompatibility complex related protein 1 (MR1). MAITs comprise up to 10% of CD8+ T cells in the peripheral blood of humans and accumulate in tissues like the liver, lung, and gut mucosa where these cells are primed to rapidly respond to microbial threats including playing a role in the initial host response to Mycobacterium tuberculosis.

• MAIT cells utilize a semi-invariant T-cell receptor (TCR) to probe ligands bound by the highly conserved MR1 molecule. Like classical major histocompatibility complex class I molecules, MR1 is expressed by all nucleated cells, but its surface expression is often limited in the absence of appropriate ligand. Upon recognition of their cognate antigen, MAITs secrete inflammatory cytokines like interferon-γ (IFN γ) and tumor necrosis factor-a (TNFa). 

• The faculty inventor developed a novel set of compounds that bind MR1 potentiating selective expansion or maintenance of MR1 T cells with microbial selectivity that could be harnessed in immunotherapeutic or vaccination strategies.     

ADVANTAGES

ADVANTAGES

• Enhanced T cell infiltration resolving effects of microbial infection

APPLICATIONS

• Immunotherapy
• Vaccine development