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Publication Abstract from PubMed

Type I Natural Killer T (NKT) cells are a population of innate like T lymphocytes that rapidly respond to alpha-GalCer presented by CD1d, via the production of both pro and anti-inflammatory cytokines. While developing novel alpha-GalCer analogs that were meant to be utilized as potential adjuvants due to their production of pro-inflammatory cytokines (Th1 skewers), we generated alpha-galactosylsphingamides (alpha-GSA). Surprisingly, alpha-GSAs are not potent antigens in vivodespite their strong T-cell receptor (TCR)-binding affinities. Here, using surface plasmon resonance (SPR), antigen presentation assays, and X-ray crystallography (yielding crystal structures of 19 different binary [CD1d-glycolipid] or ternary [CD1d-glycolipid-TCR] complexes at resolutions between 1.67 and 2.85 A), we characterized the biochemical and structural details of alpha-GSA recognition by murine NKT cells. We identified a molecular switch within murine (m)CD1d that modulates NKT cell activation by alpha-GSAs. We found that the molecular switch involves a hydrogen bond interaction between Tyr-73 of mCD1d and the amide group oxygen of alpha-GSAs. We further established that the length of the acyl chain controls the positioning of the amide group with respect to the molecular switch and works synergistically with Tyr-73 to control NKT cell activity. In conclusion, our findings reveal important mechanistic insights into the presentation and recognition of glycolipids with polar moieties in an otherwise apolar milieu.These observations may inform the development alpha-GSAs as specific NKT cell antagonists to modulate immune responses.

A molecular switch in mouse CD1d modulates natural killer T cell activation by alpha-galactosylsphingamides.,Wang J, Guillaume J, Janssens J, Remesh SG, Ying G, Bitra A, Van Calenbergh S, Zajonc DM J Biol Chem. 2019 Aug 7. pii: RA119.009963. doi: 10.1074/jbc.RA119.009963. PMID:31391251^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.