Down‐regulation of the invariant Vα14 antigen receptor in NKT cells upon activation

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Abstract
NKT cells expressing the invariant Vα14 antigen receptor constitute a novel lymphocyte subpopulation with immunoregulatory functions. Stimulation via their invariant Vα14 receptor with anti‐CD3 or a ligand, α‐galactosylceramide (α‐GalCer), triggers activation of Vα14 NKT cells, resulting in a rapid cytokine production such as IFN‐γ and IL‐4. Soon after their receptor activation, Vα14 NKT cells disappeared as judged by staining with CD1d tetramer loaded with α‐GalCer (α‐GalCer/CD1d tetramer), which has been believed to be due to apoptotic cell death. Here we show that such a disappearance was largely attributed to down‐regulation of the Vα14 receptor. In fact, Vα14 NKT cells were relatively resistant to apoptosis compared to the conventional T cells as evidenced by less staining with Annexin‐V, a limited DNA fragmentation, and their preferential expression of anti‐apoptotic genes such as NAIP and MyD118. Furthermore, they did not become tolerant, and maintained their proliferative capacity and cytokine production even after their receptor down‐regulation. These as yet unrecognized facets of Vα14 NKT cells are discussed in relation to their regulatory functions.