The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species, with a distinct set of unique biological traits conferring resistance to the spontaneous development of cancer. While, unexpectedly, it was reported that they lack natural killer (NK) cells, it has been recently suggested that naked mole-rats possess a gamma delta T cell-based immunity, that could form a main arm of the immune system involved in immunosurveillance and anticancer responses. Therefore, we investigated the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell (sc) gene expression analysis. Following a new TCR annotation in the naked mole-rat genome, we found that the gamma delta TCR repertoire is dominated by a public invariant Vgamma4-2/Vdelta1-4 TCR, containing the germline-encoded complementary-determining-region-3 (CDR3) gamma4-2 CTYWDSNYAKKLF/CDR3delta1-4 CALWELRTGGITAQLVF. Both CDR3 sequences are likely generated by short homology repeat-driven DNA rearrangements. This invariant TCR is specifically expressed by gamma delta T cells possessing NK killing machinery, while more diverse gamma delta TCRs are associated with other functional phenotypes. Finally, the invariant Vgamma4-2/Vdelta1-4 gamma delta T cells are generated in both the thoracic and cortical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vgamma4-2/Vdelta1-4 natural killer-like effector T cells in the naked mole-rat are continuously produced and can contribute to cancer immunosurveillance by gamma delta TCR-mediated recognition of a common molecular signal.
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