biostudies-literatureSidobre SNIAID NIH HHSWellcome TrustNIGMS NIH HHS12254-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC514465biostudies-literatureUnknown101(33)Natural killer (NK) T cells with an invariant Valpha14 rearrangement (Valpha14i) are the largest population of lipid antigen-specific T lymphocytes identified in animals. They react to the glycolipid alpha-galactosyl ceramide (alpha-GalCer) presented by CD1d, and they may have important regulatory functions. It was previously shown that the Valpha14i T cell antigen receptor (TCR) has a high affinity for the alpha-GalCer/CD1d complex, driven by a long half-life (t(1/2)). Although this result could have reflected the unique attributes of alpha-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of Valpha14i NKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a long t(1/2). Furthermore, our data areProceedings of the National Academy of Sciences of the United States of AmericaThe T cell antigen receptor expressed by Valpha14i NKT cells has a unique mode of glycosphingolipid antigen recognition.PMC514465R01 AI048933R01 AI45889R01 AI48933R01 AI045053U54 GM61502072021/Z/03/ZR24 GM061502R01 AI45053R01 AI045889Hammond KJMaltsev SDKronenberg MNdonye RMSakai TRichardson SKHowell ARSidobre SPorcelli SABenazet-Sidobre LBesra GSfalseThe T cell antigen receptor expressed by Valpha14i NKT cells has a unique mode of glycosphingolipid antigen recognition.Natural killer (NK) T cells with an invariant Valpha14 rearrangement (Valpha14i) are the largest population of lipid antigen-specific T lymphocytes identified in animals. They react to the glycolipid alpha-galactosyl ceramide (alpha-GalCer) presented by CD1d, and they may have important regulatory functions. It was previously shown that the Valpha14i T cell antigen receptor (TCR) has a high affinity for the alpha-GalCer/CD1d complex, driven by a long half-life (t(1/2)). Although this result could have reflected the unique attributes of alpha-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of Valpha14i NKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a long t(1/2). Furthermore, our data are2004-01-01T00:00:00Z2004 Aug2025-04-05T15:26:54.882Z2019-03-27T00:50:42ZS-EPMC5144651530464410.1073/pnas.0404632101