PT  - JOURNAL ARTICLE
AU  - Haihong Jin
AU  - Nicole A. Ladd
AU  - Andrew M. Peev
AU  - Gwendolyn M. Swarbrick
AU  - Meghan Cansler
AU  - Megan Null
AU  - Christopher T. Boughter
AU  - Curtis McMurtrey
AU  - Aaron Nilsen
AU  - Karen M. Dobos
AU  - William H. Hildebrand
AU  - Deborah A. Lewinsohn
AU  - Erin J. Adams
AU  - David M. Lewinsohn
AU  - Melanie J. Harriff
TI  - Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells
AID  - 10.1101/2022.05.11.491531
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.11.491531
4099  - http://biorxiv.org/content/early/2022/05/11/2022.05.11.491531.short
4100  - http://biorxiv.org/content/early/2022/05/11/2022.05.11.491531.full
AB  - MR1-restricted T (MR1T) cells recognize microbial small molecule metabolites presented on the MHC Class I-like molecule MR1 and have been implicated in early effector responses to microbial infection. As a result, there is considerable interest in identifying chemical properties of metabolite ligands that permit recognition by MR1T cells, for consideration in therapeutic or vaccine applications. Here, we made chemical modifications to known MR1 ligands to evaluate the effect on MR1T cell activation. Specifically, we modified 6,7-dimethyl-8-D-ribityllumazine (DMRL) to generate 6,7-dimethyl-8-D-ribityldeazalumazine (DZ), and then further derivatized DZ to determine the requirements for retaining MR1 surface stabilization and agonistic properties. Interestingly, the IFN-γ response toward DZ varied widely across a panel of T cell receptor (TCR)-diverse MR1T cell clones; while one clone was agnostic toward the modification, most displayed either an enhancement or depletion of IFN-γ production when compared with its response to DMRL. To gain insight into a putative mechanism behind this phenomenon, we used in silico molecular docking techniques for DMRL and its derivatives and performed molecular dynamics simulations of the complexes. In assessing the dynamics of each ligand in the MR1 pocket, we found that DMRL and DZ exhibit differential dynamics of both the ribityl moiety and the aromatic backbone, which may contribute to ligand recognition. Together, our results support an emerging hypothesis for flexibility in MR1:ligand-MR1T TCR interactions and enable further exploration of the relationship between MR1:ligand structures and MR1T cell recognition for downstream applications targeting MR1T cells.Competing Interest StatementThe authors have declared no competing interest.