School of Medicine

The immune system of all jawed vertebrates harbors three distinct lymphocyte populations – ab T cells, gd T cells and B cells – yet only higher primates including humans possess so-called Vg9/Vd2 T cells, an enigmatic gd T cell subset that uniformly responds to the majority of bacterial pathogens. For reasons that are not understood, this responsiveness is absent in all other animals although they too are constantly exposed to a plethora of potentially harmful micro-organisms.

i3-IRG researchers led by Dr Matthias Eberl from the Department of Infection, Immunity and Biochemistry have now investigated how Vg9/Vd2 T cells respond to live microbes by mimicking physiological conditions in acute disease. Their experiments demonstrate that Vg9/Vd2 T cells recognize a small common molecule released when invading bacteria become ingested and killed by other white blood cells. The stimulation of Vg9/Vd2 T cells at the site of infection is believed to amplify the inflammatory response and have important consequences for pathogen clearance and the development of microbe-specific immunity.

However, if triggered at the wrong time or the wrong place, this rapid reaction toward bacteria may also lead to inflammation-related damage. These findings improve our insight into the complex cellular interactions in early infection, identify novel biomarkers of diagnostic and predictive value and highlight new avenues for therapeutic intervention.

Analyses of acute episodes of bacterial infection in patients receiving peritoneal dialysis suggested a significant role for Vg9/Vd2 T cells as early responders in infection and identified a correlation between Vg9/Vd2 T cell activation and clinical outcome. This work demonstrated that the capacity of the causative pathogen to produce HMB-PP and local infiltrates of activated Vg9/Vd2 T cells are indicative of acute inflammatory responses and may predict the subsequent clinical outcome from infection.

Moreover, these investigations also provide proof of concept that the antibiotic fosmidomycin, a specific inhibitor of HMB-PP biosynthesis, may represent a promising lead for future drugs, by targeting an essential metabolic route shared by the majority of pathogenic bacteria including multidrug-resistant clinical isolates but absent in humans.  The newly published data demonstrate that a broad range of multidrug resistant Gram-negative bacteria isolated from all around the world were susceptible to fosmidomycin, at concentrations that would readily be achievable in patients.  

This research was largely conducted by the three i3-IRG PhD students Martin Davey (supervised by Dr Matthias Eberl and Prof Bernhard Moser), Chan-Yu Lin (supervised by Dr Matthias Eberl and Prof Nicholas Topley) and Jonathan Tyrrell (supervised by Dr Mark Toleman and Dr Robin Howe), in an interdisciplinary collaboration with microbiologists in London and Ireland and clinicians in Cardiff, Swansea, Stoke-on-Trent and Australia.

The main findings have been published in the following two papers:

• A promising target for treatment of multidrug-resistant bacterial infections.
  Davey MS, Tyrrell JM, Howe RA, Walsh TR, Moser B, Toleman MA, Eberl M, Antimicrob Agents Chemother (2011): in press

• Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial gammadelta T Cell Responses in Early Infection.
  Davey MS, Lin CY, Roberts GW, Heuston S, Brown AC, Chess JA, Toleman MA, Gahan CG, Hill C, Parish T, Williams JD, Davies SJ, Johnson DW, Topley N, Moser B, Eberl M. PLoS Pathogens 7 (2011):e1002040