T-cell activation by transitory neo-antigens derived from distinct microbial pathways

Area of Science:

• Immunology
• Microbiology
• Biochemistry

Background:

• T cells recognize microbial molecules, including riboflavin precursors that activate mucosal-associated invariant T (MAIT) cells.
• The synthesis and presentation of these molecules to MAIT cells by the MHC-related protein MR1 are not fully understood.

Purpose of the Study:

• To elucidate the mechanism of MAIT cell activation by microbial riboflavin precursors.
• To identify the specific molecules presented by MR1 that activate MAIT cells.

Main Methods:

• Investigated the role of genes involved in bacterial riboflavin synthesis.
• Analyzed the non-enzymatic reactions between riboflavin precursors and other small molecules.
• Determined the binding of resulting adducts to MR1 using crystal structures.
• Utilized mass spectrometry to detect antigens in bacterial cultures.

Main Results:

• MAIT cell activation requires enzymes producing 5-amino-6-d-ribitylaminouracil (5-A-RU).
• 5-A-RU forms MAIT-activating antigens (5-OE-RU and 5-OP-RU) via reactions with glyoxal and methylglyoxal.
• These antigens are captured and stabilized by MR1 as Schiff base complexes.
• Antigens were detected in MAIT cell-activating bacteria but not in non-activating ones.

Conclusions:

• MR1 presents chemically unstable pyrimidine intermediates as potent antigens to MAIT cells.
• These pyrimidine adducts serve as microbial signatures for MAIT cell immunosurveillance.
• The study reveals a novel mechanism of innate-like T cell activation and microbial detection.