Metabolic and molecular mechanisms that contribute to impaired CD4 response during Trypanosoma cruzi infection

STEMPIN, CC

Tucumán

Conferencia; LXVIII Reunión Científica Anual de la Sociedad Argentina de Inmunología.; 2019

Sociedad Argentina de Inmunología

Trypanosoma cruzi, the parasite that causes Chagas disease, was identified more than 100 years ago, however this infection is still a serious social and public health problem. The acute phase of infection is characterized by inefficient host immune response that creates a persistent infection and the establishment of chronic disease. T. cruzi-induced immunosuppression involves, among others, anergy induction and clonal deletion in T cell compartment. The relevance of T cells to control T. cruzi infection has been demonstrated in human as well as in experimental infection. Our laboratory is focus on the study of molecular and metabolic mechanism involved in CD4 T cell immunosuppression during T. cruzi experimental infection. We have previously identified the E3-Ubiquitin-Ligase GRAIL and its regulator Otubain-1 as molecular mechanism associated to CD4 T anergy during the acute phase of infection. Recent studies have shown the importance of T cell metabolism for adequate activation and effector functions. Interestingly, mitochondrial ROS (mROS) has emerged as a critical second messenger for T cell signaling and activation, however a tight regulation of mROS production by cellular antioxidant pathways is critical to maintaining proper signal transduction without compromising the integrity of the cell. It has been demonstrated that imbalances in the metabolism of T cells can generate failures in the immune response during infections, cancer and autoimmunity. However, the metabolic status of CD4 during T. cruzi infection has not been explored. We have found high frequency of mROS CD4 T cells with mitochondrial depolarization that express high levels of PD-1 during the acute phase of infection. In addition, these cells are highly oxidative with increased proton leak. We found increased antioxidant mechanisms however they may be not enough to prevent apoptosis. Then, our results indicate that infection induces mitochondrial and metabolic alteration in CD4 T cells that may have an impact in the outcome of the infection.