(E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate (HMBPP)

Short Introduction of HMBPP

HMBPP is an intermediate of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis. The enzyme HMB-PP synthase (GcpE, IspG) catalyzes the conversion of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) into HMB-PP. HMB-PP is then converted further to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).

HMB-PP is an essential metabolite in most pathogenic bacteria including mycobacterium tuberculosis as well as malaria parasites but is absent from the human host.

Fig.1 Some examples of ligands that are specifically recognized by subsets of human γδ T cells. (Kabelitz, 2017)

HMBPP and γδ T Cell

Vγ2Vδ2 T cells can be activated by metabolites from isoprenoid synthesis, such as IPP and HMBPP, which are usually referred to as phosphoantigens.

Isoprenoids are produced by one of two major pathways: the classical mevalonate pathway and the alternative, non-mevalonate pathway. IPP is an intermediate metabolite that is present in both pathways, whereas HMBPP is only produced in the non-mevalonate pathway by certain microbes such as Listeria monocytogenes (LM).

Fig.2 Immune responses and functions of HMBPP-specific Vγ2Vδ2 T cells in infections. (Zheng, 2013)

HMBPP Expansion in Macaques

Interleukin-2 (IL-2), Interleukin-15 (IL-15), or Interleukin-21 (IL-21) is needed for HMBPP-mediated expansion of Vγ2Vδ2 T cells in culture. In vivo studies have demonstrated that only HMBPP plus IL-2 cotreatment, but not IL-2 or HMBPP alone, can induce major expansion of Vγ2Vδ2 T cells in macaques.

Primary infection of macaques or humans with several viral or bacterial pathogens is incapable of producing HMBPP does not induce an appreciable expansion of Vγ2Vδ2 T cells, even though these primary infections can lead to the production of high levels of cytokines.

In a study, HMBPP plus IL-2 treatment of macaques induced a prolonged major expansion of circulating Vγ2Vδ2 T cells that expressed CD8 and produced cytotoxic perforin during their peak expansion.

HMBPP Expansion in Lung

The prolonged accumulation of Vγ2Vδ2 T cells in the lung airspaces implies that the pulmonary mucosa is the favorable migration site for phosphoantigen-specific Vγ2Vδ2 T cells. In general, the magnitude and duration of Vγ2Vδ2 T cell expansion in the lung are much greater than in the blood and gingival or rectal mucosae after the HMBPP/IL-2 cotreatment.

The preferential expression of CCR5 by pulmonary Vγ2Vδ2 T cells suggests that CCR5 may contribute to recruiting HMBPP-activated Vγ2Vδ2 T cells to the lung. This scenario is indeed supported by the in vitro migration study describing the role of CCR5 and its ligands (MIP-1α, MIP-1β, and RANTES) in the transendothelial migration of human Vγ2 T cells.

Although phosphoantigen-specific Vγ2Vδ2 T cells appear to play a role in antimicrobial and anticancer immunity, mucosal immune responses and effector functions of these γδ T cells during infection and treatment were poorly characterized. So, it is necessary to do more deeper research about γδ T cells. Creative Biolabs has committed to the research of immune cells and provides comprehensive service solutions for customers around the world. If you need our help, please contact us.

References

1. Kabelitz, D.; et al. Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins. F1000research. 2017, 6: 782.
2. Zheng, W. Chen. Multifunctional immune responses of HMBPP-specific Vγ2Vδ2 T cells in M. tuberculosis and other infections. Cellular & Molecular Immunology. 2013, 10(1).