P-C5 NKG2C+ CD8 NK-T cells–bridging the innate and adaptive immunity

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We study a special subset of CD8 T cells that expresses NK-receptors which we discovered in the past. They (CD8 NK-T cells) can be activated in two ways - through TCRs and through NK receptors. Therefore, CD8 NK-T cells bridge the innate and adaptive arms of the immune response. Infectious viruses employ various strategies to evade killing actions by NK and CD8 T cells. However, CD8 NK-T cells seem impervious to typical interference by viruses and can be exploited as a front line defense against chronic virus infections.


NKG2C belongs to the lectin family and transduces a true activating signal, unlike NKG2D which only provides a co-stimulatory signal. NKG2C+CD8 NK-T cells is a minor subset (1~5% in CD8 T cells), and do not express typical inhibitory receptors (NKG2A, KIR2L1, LAG3, 2B4, Tim3, or CTLA4) so not easily suppressed by regular mechanisms once activated. Engagement of NKG2C specifically augmented cytotoxicity of these cells against target cells independent of specific antigen. In parallel, typical T cell activation (PHA, PMA, anti-CD3/CD28) also augmented a potent cytotoxicity. Curiously, antigen-stimulation caused a transient upregulation of PD-1, a checkpoint molecule, which terminated the TCR-mediated killing of these cells in the long run. However, the NKG2C-induced cytotoxicity was not affected by the PD-1 engagement. Thus NKG2C+ CD8 NK-T cells uses the PD-1 system as a molecular switch to choose between the innate and adaptive modes of target killing.


Despite its unique nature, NKG2C CD8 NK-T cells have not been well-characterized. Our study provides a potential of these cells as a versatile killer which operates in the innate and adaptive modes and are more resistant to the immune evasion by viruses. Previous studies show their role in the CMV infection. Ex vivo expansion and arming with self-activating HLA-E molecule of these cells may help develop a potent cellular defense against persistent infections including that by HIV.

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