Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming

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 suc...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-11, Vol.197 (10), p.3959-3969
Main Authors: Cruz Tleugabulova, Mayra, Escalante, Nichole K, Deng, Shenglou, Fieve, Stephanie, Ereño-Orbea, June, Savage, Paul B, Julien, Jean-Philippe, Mallevaey, Thierry
Format: Article
Language:English
Subjects:
Animals
Antigens - immunology
Antigens, CD1d - immunology
Antigens, CD1d - metabolism
Cell Differentiation
Cytokines - biosynthesis
Cytokines - immunology
Half-Life
Kinetics
Lipids - immunology
Lymphocyte Activation
Mice
Natural Killer T-Cells - immunology
Natural Killer T-Cells - physiology
Protein Binding
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - metabolism
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1601382