GRAIL and Otubain are related to T cell hyporesponsiveness during Trypanosoma cruzi infection

Abstract

Trypanosoma cruzi infection is associated with severe T cell unresponsiveness to antigens and mitogens and is characterized by decreased IL-2 synthesis. On the other hand, acquisition of the anergic phenotype correlated with upregulation of gene related to anergy in lymphocytes (GRAIL) protein in CD4 T cells. We therefore sought to examine the role of GRAIL in CD4 T cell proliferation during T. cruzi infection.Methodology/Principal Findings We sought to examine the role of GRAIL in CD4 T cell proliferation during T. cruzi experimental infection. Balb/c mice were infected intraperitoneally with 500 blood derived trypomastigotes of Tulahuen strain, and spleen cells from control non-infected or infected animals were obtained. CD4 T cell proliferation was assessed by CFSE staining, and the expression of GRAIL in splenic T cells was measured by real-time PCR, flow cytometry and Western blot. We found an increased GRAIL expression at the early stages of infection, coincident with impaired proliferation and poor IL-2 and IFN- secretion in response to plate bound antibodies. In addition, we showed that the expression of GRAIL E3-ubiquitin ligase in CD4+ T cells during the acute phase of infection was complemented by a high expression of inhibitory receptors such as PD-1 and CTL-4. Moreover, we demonstrated that GRAIL expression during infection was regulated by IL-2 since it was able to activate the mammalian target of the rapamycin (mTOR) pathway, inducing Otubain-1 expression that mediated GRAIL degradation and improved T cell proliferation.