Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells
Abstract 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 metaboli...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-12-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-26259-y |
| _version_ | 1797973619391856640 |
|---|---|
| author | Haihong Jin Nicole A. Ladd Andrew M. Peev Gwendolyn M. Swarbrick Meghan Cansler Megan Null Christopher T. Boughter Curtis McMurtrey Aaron Nilsen Karen M. Dobos William H. Hildebrand Deborah A. Lewinsohn Erin J. Adams David M. Lewinsohn Melanie J. Harriff |
| author_facet | Haihong Jin Nicole A. Ladd Andrew M. Peev Gwendolyn M. Swarbrick Meghan Cansler Megan Null Christopher T. Boughter Curtis McMurtrey Aaron Nilsen Karen M. Dobos William H. Hildebrand Deborah A. Lewinsohn Erin J. Adams David M. Lewinsohn Melanie J. Harriff |
| author_sort | Haihong Jin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T04:07:08Z |
| format | Article |
| id | doaj.art-2922d25154b844d9be6d978cad284414 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T04:07:08Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2922d25154b844d9be6d978cad2844142023-01-01T12:18:11ZengNature PortfolioScientific Reports2045-23222022-12-0112111610.1038/s41598-022-26259-yDeaza-modification of MR1 ligands modulates recognition by MR1-restricted T cellsHaihong Jin0Nicole A. Ladd1Andrew M. Peev2Gwendolyn M. Swarbrick3Meghan Cansler4Megan Null5Christopher T. Boughter6Curtis McMurtrey7Aaron Nilsen8Karen M. Dobos9William H. Hildebrand10Deborah A. Lewinsohn11Erin J. Adams12David M. Lewinsohn13Melanie J. Harriff14Medicinal Chemistry Core, Oregon Health & Science UniversityDepartment of Biochemistry and Molecular Biology, University of ChicagoDepartment of Biochemistry and Molecular Biology, University of ChicagoDivision of Infectious Diseases, Department of Pediatrics, Oregon Health & Science UniversityDivision of Infectious Diseases, Department of Pediatrics, Oregon Health & Science UniversityDivision of Infectious Diseases, Department of Pediatrics, Oregon Health & Science UniversityGraduate Program in Biophysical Sciences, University of ChicagoPureMHC LLCMedicinal Chemistry Core, Oregon Health & Science UniversityDepartment of Microbiology, Immunology, and Pathology, Colorado State UniversityDepartment of Microbiology and Immunology, University of Oklahoma Health Sciences CenterDivision of Infectious Diseases, Department of Pediatrics, Oregon Health & Science UniversityDepartment of Biochemistry and Molecular Biology, University of ChicagoDivision of Infectious Diseases, Department of Pediatrics, Oregon Health & Science UniversityVA Portland Health Care SystemAbstract 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.https://doi.org/10.1038/s41598-022-26259-y |
| spellingShingle | Haihong Jin Nicole A. Ladd Andrew M. Peev Gwendolyn M. Swarbrick Meghan Cansler Megan Null Christopher T. Boughter Curtis McMurtrey Aaron Nilsen Karen M. Dobos William H. Hildebrand Deborah A. Lewinsohn Erin J. Adams David M. Lewinsohn Melanie J. Harriff Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells Scientific Reports |
| title | Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells |
| title_full | Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells |
| title_fullStr | Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells |
| title_full_unstemmed | Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells |
| title_short | Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells |
| title_sort | deaza modification of mr1 ligands modulates recognition by mr1 restricted t cells |
| url | https://doi.org/10.1038/s41598-022-26259-y |
| work_keys_str_mv | AT haihongjin deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT nicolealadd deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT andrewmpeev deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT gwendolynmswarbrick deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT meghancansler deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT megannull deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT christophertboughter deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT curtismcmurtrey deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT aaronnilsen deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT karenmdobos deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT williamhhildebrand deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT deborahalewinsohn deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT erinjadams deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT davidmlewinsohn deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells AT melaniejharriff deazamodificationofmr1ligandsmodulatesrecognitionbymr1restrictedtcells |