According to the authors Pierre Guermonprez, Michael Nussenzweig and colleagues at the Rockefeller University, New York, Flt3l regulates the expansion of dendritic cells during all developmental stages but its role in dendritic cell differentiation during acute infection is less well known. Early during malaria, upregulation of IFNα mediated the increase of xanthine dehydrogenase that converts hypoxanthine and xanthine to uric acid. Accumulation of uric acid in plasma and in infected erythrocytes led to the release of Flt3l from mast cells, which in turn induced the expansion of CD8α+ CD103+ dendritic cells. These dendritic cells are essential for the activation of CD8+ T cells.
In collaboration with Britta Urban at LSTM and the KEMRI-Wellcome Trust Research Programme, the authors showed that Flt3l is increased in children with severe malaria and correlated with the increase of BDCA3+ dendritic cells (the equivalent of CD8a+CD103+ dendritic cells in rodents) in peripheral blood suggesting that a similar pathway of Flt3l-mediated dendritic cell expansion is activated during human malaria.
Importantly, the activation of CD8+ T cells during bloodstage infection has been linked with both pathology and protection from severe disease in rodent models. By contrast, the role CD8+ T cell during blood stage infection in humans has received very little attention but may be equally relevant for the balance between immune-mediated protection from or pathology of severe disease.