The immune suppression that characterizes human helminth
infections can hinder the development of protective immunity or help to reduce pathogenic
inflammation. Signaling through the T cell costimulator
glucocorticoid-induced TNFR-related protein (GITR) counteracts immune downregulation by augmenting effector T cell responses and abrogating suppression by Foxp3(+) regulatory T cells. Thus, superphysiological Ab-mediated GITR costimulation represents a novel
therapy for promoting protective immunity toward parasitic helminths, whereas blocking physiological GITR-GITR
ligand (GITRL) interactions may provide a mechanism for dampening pathogenic Th2
inflammation. We investigated the superphysiological and physiological roles of the GITR-GITRL pathway in the development of protective and pathogenic Th2 responses in murine
infection models of
filariasis (Litomosoides sigmodontis) and
schistosomiasis (Schistosoma mansoni). Providing superphysiological GITR costimulation using an agonistic anti-GITR mAb over the first 12 d of L. sigmodontis
infection initially increased the quantity of Th2 cells, as well as their ability to produce Th2
cytokines. However, as
infection progressed, the Th2 responses reverted to normal
infection levels, and parasite killing remained unaffected. Despite the Th2-promoting role of superphysiological GITR costimulation, Ab-mediated blockade of the GITR-GITRL pathway did not affect Th2 cell priming or maintenance during L. sigmodontis
infection. Blockade of GITR-GITRL interactions during the acute egg phase of S. mansoni
infection resulted in reduced Th2 responses, but this effect was confined to the spleen and did not lead to changes in liver pathology. Thus, although superphysiological GITR costimulation can therapeutically enhance Th2 responses, physiological GITR-GITRL interactions are not required for the development of Th2-mediated resistance or pathology in murine models of
filariasis and
schistosomiasis.