Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids
Abstract α-Galactosylceramide (α-GalCer) is a prototypical antigen recognized by natural killer T (NKT) cells, a subset of T cells crucial for immune regulation. Despite its significance, the complex structure-activity relationship of α-GalCer and its analogs remains poorly understood, particularly...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01497-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849733295687860224 |
|---|---|
| author | Jesang Lee Sumin Son Minha Lee Seung Bum Park |
| author_facet | Jesang Lee Sumin Son Minha Lee Seung Bum Park |
| author_sort | Jesang Lee |
| collection | DOAJ |
| description | Abstract α-Galactosylceramide (α-GalCer) is a prototypical antigen recognized by natural killer T (NKT) cells, a subset of T cells crucial for immune regulation. Despite its significance, the complex structure-activity relationship of α-GalCer and its analogs remains poorly understood, particularly in defining the structural determinants of NKT cell responses. In this study, we designed and synthesized potential immunomodulatory ligands targeting NKT cells, inspired by glycolipids derived from the gut symbiont Bacteroides fragilis. A series of α-GalCer analogs with terminal iso-branched sphinganine backbones was developed through rational modification of the acyl chain. Our results identified the C3′ hydroxyl group as a structural element that impairs glycolipid presentation by CD1d, as evidenced by reduced IL-2 secretion and weak competition with a potent CD1d ligand. Notably, among C3′-deoxy α-GalCer analogs, those containing an α-chloroacetamide group exhibited robust NKT cell activation with Th2 selectivity. Computational docking and mass spectrometry analyses further confirmed the substantial interaction of α-chloroacetamide analogs to CD1d. These findings underscore the potential of leveraging microbiota-derived glycolipid structures to selectively modulate NKT cell functions for therapeutic purposes. |
| format | Article |
| id | doaj-art-ae8a0930b51e4a7fa1a524cb7b48bf14 |
| institution | DOAJ |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-ae8a0930b51e4a7fa1a524cb7b48bf142025-08-20T03:08:05ZengNature PortfolioCommunications Chemistry2399-36692025-04-01811910.1038/s42004-025-01497-zDevelopment of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipidsJesang Lee0Sumin Son1Minha Lee2Seung Bum Park3Department of Chemistry, Seoul National UniversityDepartment of Chemistry, Seoul National UniversityDepartment of Chemistry, Seoul National UniversityDepartment of Chemistry, Seoul National UniversityAbstract α-Galactosylceramide (α-GalCer) is a prototypical antigen recognized by natural killer T (NKT) cells, a subset of T cells crucial for immune regulation. Despite its significance, the complex structure-activity relationship of α-GalCer and its analogs remains poorly understood, particularly in defining the structural determinants of NKT cell responses. In this study, we designed and synthesized potential immunomodulatory ligands targeting NKT cells, inspired by glycolipids derived from the gut symbiont Bacteroides fragilis. A series of α-GalCer analogs with terminal iso-branched sphinganine backbones was developed through rational modification of the acyl chain. Our results identified the C3′ hydroxyl group as a structural element that impairs glycolipid presentation by CD1d, as evidenced by reduced IL-2 secretion and weak competition with a potent CD1d ligand. Notably, among C3′-deoxy α-GalCer analogs, those containing an α-chloroacetamide group exhibited robust NKT cell activation with Th2 selectivity. Computational docking and mass spectrometry analyses further confirmed the substantial interaction of α-chloroacetamide analogs to CD1d. These findings underscore the potential of leveraging microbiota-derived glycolipid structures to selectively modulate NKT cell functions for therapeutic purposes.https://doi.org/10.1038/s42004-025-01497-z |
| spellingShingle | Jesang Lee Sumin Son Minha Lee Seung Bum Park Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids Communications Chemistry |
| title | Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids |
| title_full | Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids |
| title_fullStr | Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids |
| title_full_unstemmed | Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids |
| title_short | Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids |
| title_sort | development of potential immunomodulatory ligands targeting natural killer t cells inspired by gut symbiont derived glycolipids |
| url | https://doi.org/10.1038/s42004-025-01497-z |
| work_keys_str_mv | AT jesanglee developmentofpotentialimmunomodulatoryligandstargetingnaturalkillertcellsinspiredbygutsymbiontderivedglycolipids AT suminson developmentofpotentialimmunomodulatoryligandstargetingnaturalkillertcellsinspiredbygutsymbiontderivedglycolipids AT minhalee developmentofpotentialimmunomodulatoryligandstargetingnaturalkillertcellsinspiredbygutsymbiontderivedglycolipids AT seungbumpark developmentofpotentialimmunomodulatoryligandstargetingnaturalkillertcellsinspiredbygutsymbiontderivedglycolipids |