Phosphoantigens (PAgs)

Introduction of PAg

The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called pAgs that are present in infected cells or accumulate intracellularly in certain tumor cells. Vγ9/Vδ2 T cells respond specifically to pAg, such as the microbial isoprenoid precursor (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), shared by many Gram-negative and Gram-positive bacteria as well as malaria parasites; and at much higher concentrations, Vγ9/Vδ2 T cells respond to the related metabolite isopentenyl pyrophosphate (IPP), which is present in all living prokaryotic and eukaryotic cells. Other ligands for Vδ2Vγ9 T cells include the ectopically expressed DNA mismatch repair protein hMSH and F1-ATPase together with apolipoprotein A-I.

Fig.1 Different classes of proposed and confirmed γδ T cell ligands. (Vermijlen, 2018)

PAg and γδ T Cells

In vitro assays that rely on the incubation of peripheral lymphoid cells with mycobacterial lysates have evidenced Vγ9Vδ2 T cell expansion is mediated by protease-resistant and pAg. A member of the transmembrane butyrophilin (BTN) proteins was required for the activation of human γδ T cells by microbial or endogenous pAg.

The clear evidence shows that butyrophilin-3A (BTN3A/CD277) molecules play a mandatory role in the antigenic activation of primate Vγ9Vδ2 T cells. BTN3A has three isoforms: BTN3A1, BTN3A2, and BTN3A3 which have high structural homology to the B7 superfamily of proteins and exist as V-shaped homodimers in solution, associating through the membrane proximal C-type Ig domain. This kind of structures in a certain way directly demonstrates that BTN3A1 is necessary for Vγ9Vδ2 activation and begins to unravel the extracellular events that occur during stimulation through the Vγ9Vδ2 T cell receptor.

By generating a panel of activating or inhibitory anti-CD277 monoclonal antibodies (mAbs), scientists uncovered that certain activating anti-CD277 mAbs induced a selective and exclusive activation and proliferation of Vγ9Vδ2 T cells when added to in vitro cultures of peripheral blood lymphocytes, similar to what is seen when phosphoantigens are used for in vitro stimulation.

Fig.2 Role of CD277/butyrophilin-3A in triggering human γδ T-cell activation. (Kabelitz, 2010)

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References

1. Vermijlen, David.; et al. γδ T cell responses: How many ligands will it take till we know? Seminars in cell & developmental biology. 2018, 84.
2. Kabelitz, D. CD277 takes the lead in human γδ T-cell activation. Blood. 2012, 120(11): 2159.