TCR density in early iNKT cell precursors regulates agonist selection and subset differentiation in mice
Claudine Josepha b c, Jihène Klibia b c✉, Ludivine Amablea b, Lorenzo Combaa b, Alessandro Cascioferrod, Marc Delorde, Véronique Pariettib f, Christelle Lenoirg h i, Sylvain Latourg h i, Bruno Lucasj, Christophe Viretk l m n, Antoine Touberta b, Kamel Benlaghaa b✉
- aINSERM, UMR‐1160 Institut Universitaire d'Hématologie Paris France
- bUniversité Paris Diderot Sorbonne Paris Cité Paris France
- cThese authors equally contributed to this article
- dUnité de Pathogénomique Mycobactérienne Intégrée Institut Pasteur Paris France
- ePlateforme de Bio‐informatique et Bio statistique Institut Universitaire d'Hématologie Université Paris Diderot Sorbonne Paris Cité Paris France
- fDépartement d'Expérimentation Animale Institut Universitaire d'Hématologie Paris France
- gImagine Institut Université Paris Diderot Sorbonne Paris Cité Paris France
- hLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Paris France
- iLaboratory of Lymphocyte Activation and Susceptibility to EBV infection, Paris, France
- jInstitut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016 Université Paris Descartes Paris France
- k
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Abstract
It is established that iNKT cells are a cell type that require strong TCR signal for their proper development and represent a model for thymic agonist selection. The nature of the signal perceived by iNKT cells promoting their specification is not well understood. To address this question, we analyzed iNKT cell development in relevant TCR Vα14-Jα18 alpha chain transgenic mice (Vα14Tg). In CD4-Vα14Tg mice, where the transgene is driven by CD4 promoter, we identified a block in iNKT cell development at early developmental stages due to a reduced expression of key transcription factors accompanied with a reduced TCR expression levels. This indicates that TCR signal strength control iNKT cell differentiation. Importantly, we found in WT mice that early precursors of iNKT cells express higher TCR levels compared to positively selected precursors of mainstream T cells showing that TCR levels could contribute to the strength of iNKT cell TCR signaling. Overall, our study highlights TCR signal strength associated with a higher TCR density as an important regulator of iNKT cell lineage specification.