title: Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming.
abstract: Invariant NKT (iNKT) cells develop and differentiate in the thymus, segregating into iNKT1/2/17 subsets akin to Th1/2/17 classical CD4+T cells; however, iNKT TCRs recognize Ags in a fundamentally different way. How the biophysical parameters of iNKT TCRs influence signal strength in vivo and how such signals affect the development and differentiation of these cells are unknown. In this study, we manipulated TCRs in vivo to generate clonotypic iNKT cells using TCR retrogenic chimeras. We report that the biophysical properties of CD1d-lipid-TCR interactions differentially impacted the development and effector differentiation of iNKT cells. Whereas selection efficiency strongly correlated with TCR avidity, TCR signaling, cell-cell conjugate formation, and iNKT effector differentiation correlated with the half-life of CD1d-lipid-TCR interactions. TCR binding properties, however, did not modulate Ag-induced iNKT cytokine production. Our work establishes that discrete TCR interaction kinetics influence iNKT cell development and central priming.
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Mayra
authors: 0000-0001-8105-856X
authors: M
authors: Cruz Tleugabulova
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Nichole K
authors: NK
authors: Escalante
authors: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602.
authors: Shenglou
authors: S
authors: Deng
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Stephanie
authors: S
authors: Fieve
authors: The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; and.
authors: June
authors: 0000-0001-8982-1857
authors: J
authors: Ereño-Orbea
authors: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602.
authors: Paul B
authors: PB
authors: Savage
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; and.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Jean-Philippe
authors: JP
authors: Julien
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; thierry.mallevaey@utoronto.ca.
authors: Thierry
authors: T
authors: Mallevaey
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006207:Half-Life; D007700:Kinetics; D008055:Lipids / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000502:physiology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
chemical_list: D000941:Antigens; D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D016207:Cytokines; D008055:Lipids; D011948:Receptors, Antigen, T-Cell