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Abstract

Natural killer T (NKT) cell development depends on recognition of self-glycolipids via their semi-invariant V alpha 14i-TCR. However, to what extent TCR-mediated signals determine identity and function of mature NKT cells remains incompletely understood. To address this issue, we developed a mouse strain allowing conditional V alpha 14i-TCR expression from within the endogenous Tcr alpha locus. We demonstrate that naive T cells are activated upon replacement of their endogenous TCR repertoire with V alpha 14i-restricted TCRs, but they do not differentiate into NKT cells. On the other hand, induced TCR ablation on mature NKT cells did not affect their lineage identity, homeostasis, or innate rapid cytokine secretion abilities. We therefore propose that peripheral NKT cells become unresponsive to and thus are independent of their autoreactive TCR.