Work

Development of potential immunomodulatory ligands targeting natural killer T cells inspired by gut symbiont-derived glycolipids

Year: 2025

Type: article

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. α-GalCer is a prototypical antigen recognized by NKT cells, which is involved in immune regulation, however, the structure-activity relationships of α-GalCer and its analogs remain poorly understood. Here, the authors synthesize a series of α-GalCer analogs, inspired by glycolipids derived from the gut symbiont B. fragilis, and reveal that a C3′-deoxy α-GalCer containing an α-chloroacetamide group exhibits robust NKT cell activation with Th2 selectivity.

Source: Communications Chemistry

DOI: 10.1038/s42004-025-01497-z

Authors: Jesang Lee, Sumin Son, Minha Lee, Seung Bum Park

Institution: Seoul National University

Language: English

Topic: Carbohydrate Chemistry and Synthesis

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,690