Non-peptidic antigen

Non-peptidic antigens are low molecular weight compounds that stimulate human Vγ9/Vδ2 T cells. The most potent activator for Vγ9/Vδ2 T cells is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a natural intermediate of the non-mevalonate pathway of isopentenyl pyrophosphate (IPP) biosynthesis. HMB-PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis as well as in malaria parasites, but is absent from the human host.

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IPP itself is structurally closely related to HMB-PP and ubiquitously present in all living cells (i.e. also in human cells), yet its potency in vitro is 10,000-fold reduced; whether IPP represents a physiological 'danger' signal of stressed or transformed cells is still unclear.

Of pharmacological interest and with bioactivities comparable to that of IPP are synthetic aminobisphosphonates such as zoledronate (Zometa^®) that are widely used to treat osteoporosis and bone metastases, and incidentally act as Vγ9/Vδ2 T cell receptor agonists.

Finally, certain alkylated amines have been described to activate Vγ9/Vδ2 T cells in vitro, however only at millimolar concentrations, i.e. with potencies 10⁶-fold to 10⁸-fold lower than those of HMB-PP, thereby questioning their physiological relevance.

References

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2. Eberl M, Hintz M, Reichenberg A, Kollas AK, Wiesner J, Jomaa H. Microbial isoprenoid biosynthesis and human γδ T cell activation. FEBS Lett. 2003;544:4-10. PMID 12782281
3. Holtmeier W, Kabelitz D. γδ T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151-83. PMID 15976493
4. Girardi M. Immunosurveillance and immunoregulation by γδ T cells. J Invest Dermatol. 2006 Jan;126:25-31. PMID 16417214