Innate immunity: Chemokine mimic is STAg's secret ingredient

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A parasite protein has been identified that can activate dendritic cells through a chemokine receptor.

Activation of cell-mediated immunity by the protozoan intracellular parasite Toxoplasma gondii is essential for control of infection and long-lived immunity. Now researchers have identified what seems to be a crucial initiator of this response — a parasite protein that can activate dendritic cells (DCs) through a chemokine receptor.

Infection with T. gondii is widespread throughout the world and, although it can cause devastating encephalitic disease in immunosuppressed individuals, it is usually asymptomatic. Infection leads to the rapid induction of interleukin-12 (IL-12) production by DCs, which triggers a T helper 1 (T_H1) response that controls the acute infection but then subsides, allowing the maintenance of inactive parasites in tissue cysts, often for the life of the host.

Tachyzoites — the parasite stage that multiplies and destroys host cells — are known to produce IL-12-inducing soluble factors but, until now, the specific molecule(s) had not been characterized. To pinpoint this factor(s), Julio Aliberti and colleagues fractionated tachyzoite supernatant (instead of the more complex and more commonly used soluble tachyzoite extract, known as STAg). A single protein with IL-12-inducing activity was isolated and identified as a cyclophilin known as C18.

Cyclophilins are peptidyl propyl isomerases that are thought to be involved in protein folding; C18 is the first cyclophilin reported to have immunostimulatory properties. Notably, cyclophilins from the related malaria parasite Plasmodium falciparum and from humans did not share the potent IL-12-inducing capacity of C18. Although C18 was less potent than STAg or tachyzoite supernatant in inducing the production of IL-12 by DCs, C18-specific antibodies almost completely inhibited STAg-induced IL-12 production by DCs.

Previously, this group had shown that MYD88, an adaptor of Toll-like receptor (TLR) signalling, and the chemokine receptor CCR5 were required for the maximal induction of IL-12 production by STAg. To find out whether C18 engages these pathways, DCs from MYD88- or CCR5-deficient mice were stimulated with STAg or C18. Responses to STAg were reduced in both cases, but only CCR5-deficient DCs had defective responses to C18. This shows that C18 signals specifically through CCR5 and indicates the presence of at least one other IL-12-inducing factor that operates through a MYD88-dependent pathway. C18 was also shown to act as a chemoattractant for DCs both in vitro and in vivo.

The identity of the additional MYD88-dependent IL-12-inducing factor(s) is an important area for future study. In addition, it is possible that C18 requires a cofactor for full activity and the authors are now following up preliminary evidence that parasite-derived peptides might augment the IL-12-inducing capacity of C18.

Jennifer Bell

References

Aliberti, J. et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nature Immunol. 4, 485–490 (2003) | Article | PubMed |

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Alan Sher's lab

The Toxoplasma gondii genome project