Abstract
Author SummaryCertain lineages of T cells can recognize lipids as stimulatory antigens when presented in the context of CD1 molecules. We know how most Natural Killer T (NKT) cells react with this unusual ligand because they use a single invariant T cell receptor (TCR) alpha chain to do the job. NKT cells place particular emphasis on their CDR3α and CDR2β loops in recognition of antigen—these complementarity determining regions (CDRs) are the hypervariable parts of the TCR that “complement” an antigen's shape. How do these other T cells recognize closely related yet distinct lipid antigens? Here we show that human CD1d-restricted T cells, typically called Vα24− T cells due to their use of diverse Vα domains in their TCRs, use similar molecular strategies to respond to lipid antigens presented by CD1d. To this end we present a 2.5 Å complex structure of a Vα24− TCR complexed with CD1d presenting the protypical lipid, α-galactosylceramide (αGalCer). The TCR examined in this study notably shifts its binding slightly, placing more emphasis on the interaction with the CDR1α loop as revealed through alanine scanning mutagenesis. This shift explains the inability of these T cells to respond to lipids that vary at this site of contact (the 4'OH), like the related α-linked glucosylceramide. These results provide a molecular basis for the fine-specificity of different CD1d-restricted T cell lineages.
Highlights
Natural killer T (NKT) cells are a highly conserved lineage of T lymphocytes found in both human and mice that are involved in the modulation of the immune response in autoimmunity, infection, and tumor development [1]
We know how most Natural Killer T (NKT) cells react with this unusual ligand because they use a single invariant T cell receptor (TCR) alpha chain to do the job
NKT cells place particular emphasis on their CDR3a and CDR2b loops in recognition of antigen—these complementarity determining regions (CDRs) are the hypervariable parts of the TCR that ‘‘complement’’ an antigen’s shape. How do these other T cells recognize closely related yet distinct lipid antigens? Here we show that human CD1d-restricted T cells, typically called Va242. Despite the TCR J24N.22 (Va242) T cells due to their use of diverse Va domains in their TCRs, use similar molecular strategies to respond to lipid antigens presented by CD1d
Summary
Natural killer T (NKT) cells are a highly conserved lineage of T lymphocytes found in both human and mice that are involved in the modulation of the immune response in autoimmunity, infection, and tumor development [1]. NKT cells expressing these TCRs have a pre-activated phenotype that is due to the expression of the transcription factor pro-myelocytic leukemia zinc finger (PLZF) [5,6] and are characterized by high reactivity towards the potent stimulatory lipid antigen a-galactosylceramide (aGalCer) [7] In both humans and mice there are additional classes of T cells that respond to CD1d, one that expresses diverse TCRs but do not respond to aGalCer; these are generally called Type II or non-invariant NKT cells [8]. These cells are called Va10 NKT cells and show a preference for a-glucosylceramide (aGlcCer) over aGalCer; Va10 NKT cells can produce a several magnitudes greater cytokine response relative to iNKT cells when stimulated by the related a-glucuronosyldiacylglycerl (a-GlcA-DAG) [11]
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