Journal
JOURNAL OF IMMUNOLOGY
Volume 171, Issue 9, Pages 4539-4551Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.171.9.4539
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL054977] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI042284, R21AI042284] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL54977] Funding Source: Medline
- NIAID NIH HHS [AI42284] Funding Source: Medline
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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 a-galactosylceramide (a-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 aGalCer 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.
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