Phosphoantigens (PAgs)

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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.

Different classes of proposed and confirmed γδ T cell ligands. 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.

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

γδ T cell, a group of immune cells that exhibit features from both innate and adaptive immunity, possesses significant potential in clinical applications such as the treatment of microbial infections and cancer immunotherapy. To fully understand their biology and harness them, Creative Biolabs can provide our worldwide customers with high-quality services in terms of γδ T cell. Our outstanding scientists will do their best to meet every customer's requirements. If you have any questions, please contact us.


  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.
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