In Vivo Manipulation of γ9+ T Cells in the Common Marmoset (Callithrix Jacchus) with Phosphoantigen and Effect on the Progression of Respiratory Melioidosis

Abstract

Burkholderia pseudomallei is a dangerous human pathogen. Phosphoantigens specifically the target primate specific γ9+δ2+ T cells subset and some have been developed as potential immunotherapeutics. Previously, we demonstrated that, when stimulated with the phosphoantigen CHDMAPP, γ9+δ2+ T cells aid in the killing of intracellular B. pseudomallei bacteria. Moreover, we found that common marmoset (Callithrix Jacchus) γ9+ T cells increase in frequency and respond to the phosphoantigen CHDMAPP and/or B. pseudomallei, in combination with IL-2, in a similar manner to human γ9+δ2+ T cells. Here we evaluate the efficacy of the phosphoantigen CHDMAPP, in combination with IL-2, as a therapy against B. pseudomallei infection, in vivo. We found that the previous studies predicted the in vivo responsiveness of γ9+ T cells to the CHDMAPP+IL-2 treatment and significant expansion of the numbers of peripheral and splenic γ9+ T cells were observed. This effect was similar to those reported in other primate species treated with phosphoantigen. Furthermore, splenocytes were retrieved 7 days post onset of treatment, restimulated with CHDMAPP or heat-killed B. pseudomallei and the cultured γ9+ T cells demonstrated no reduction in IFN-γ response when CHDMAPP+IL-2 animals were compared to IL-2 only treated animals. Using an established model of B. pseudomallei infection in the marmoset, we assessed the potential for using phosphoantigen as a novel immunotherapy. The CHDMAPP treatment regime had no effect on the progression of respiratory melioidosis and this was despite the presence of elevated numbers of γ9+ T cells in the spleen, liver and lung and an increased proportion of IFN-γ+ cells in response to infection. We therefore report that the common marmoset has proven a good model for studying the effect in vivo of γ9+ T cell stimulation; however, γ9+ T cells have little or no effect on the progression of lethal, respiratory B. pseudomallei infection. © 2013 Laws et al.