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Va14Ja18 natural T (iNKT) cells rapidly elicit a robust effector response to different glycolipid Ags, with distinct functional outcomes. Biochemical parameters controlling iNKT cell function are partly defined. However, the impact of iNKT cell receptor beta-chain repertoire and how alpha-galactosylceramide (alpha-GalCer) analogues induce distinct functional responses have remained elusive. Using altered glycolipid ligands, we discovered that the Vb repertoire of iNKT cells impacts recognition and Ag avidity, and that stimulation with suboptimal avidity Ag results in preferential expansion of high-affinity iNKT cells. iNKT cell proliferation and cytokine secretion, which correlate with iNKT cell receptor down-regulation, are induced within narrow biochemical thresholds. Multimers of CD1d1-alphaGalCer- and alphaGalCer analogue-loaded complexes demonstrate cooperative engagement of the Va14Ja18 iNKT cell receptor whose structure and/or organization appear distinct from conventional alphabeta TCR. Our findings demonstrate that iNKT cell functions are controlled by affinity thresholds for glycolipid Ags and reveal a novel property of their Ag receptor apparatus that may have an important role in iNKT cell activation.

Original publication

DOI

10.4049/jimmunol.171.9.4539

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

11/2003

Volume

171

Pages

4539 - 4551

Addresses

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Keywords

Killer Cells, Natural, T-Lymphocyte Subsets, Cell Line, Clone Cells, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Sphingosine, Galactosylceramides, Receptors, Antigen, T-Cell, alpha-beta, Antigens, CD1, Antigens, Cytotoxicity Tests, Immunologic, Sensitivity and Specificity, Lymphocyte Activation, Structure-Activity Relationship, Kinetics, Antigens, CD1d