Differential antigenic requirements by diverse MR1-restricted T cells

Area of Science:

• Immunology
• T-cell biology
• Cancer immunology

Background:

• The Major Histocompatibility Complex (MHC)-related protein 1 (MR1) presents microbial metabolites to mucosal-associated invariant T (MAIT) cells.
• Diverse MR1-restricted T cells recognize tumor cells, potentially via tumor-derived self-antigens, but these remain unidentified.
• Understanding MR1-restricted T cell recognition is key for cancer immunotherapy.

Purpose of the Study:

• To investigate the MR1 restriction and antigen reactivity of various MR1-restricted T cell receptors (TCRs), including those targeting tumors.
• To elucidate the structural basis of TCR binding to MR1 and identify factors influencing tumor cell recognition.

Main Methods:

• TCR gene transfer into T cells.
• Engineering MR1-expressing antigen-presenting cells.
• Utilizing MR1-mutant cell lines to map TCR-binding interfaces.
• Competitive inhibition assays with MR1 ligands.

Main Results:

• Confirmed MR1 reactivity for a range of MR1-restricted TCRs, with varying dependence on MR1's lysine at position 43 (K43).
• Demonstrated competitive inhibition by the MR1 ligand 6-formylpterin.
• MR1-mutant cell lines revealed distinct MR1 residues on α1/α2 helices critical for different TCR bindings.
• TCR-reporter lines did not replicate previously reported tumor specificity, highlighting the role of accessory molecules.

Conclusions:

• MR1-restricted T cells recognize diverse antigens, not solely microbial metabolites.
• Accessory molecules are vital for MR1-dependent tumor cell recognition, beyond TCR-MR1 interactions.
• Distinct TCR docking modes on MR1 suggest a broad recognition capacity within MR1-restricted T cells.