Lanterna Rally

Author: Heather Hartig Pua

Publisher:

Published: 2008

Total Pages: 260

ISBN-13:

T cell survival is a carefully regulated processes which impacts T cell development, peripheral homeostasis and immune responses. Although the lysosomally-mediated catabolic process of autophagy was identified decades ago in tissue specimens, only recently has the core molecular machinery responsible for autophagy been identified. An explosion of work has followed characterizing the role of autophagy in metabolism, organelle homeostasis, cell death, oncogenesis, innate immunity, and MHCII cross presentation. Given the emerging role for autophagy in cell survival as well as the critical regulation of death in T lymphocytes, we hypothesized that autophagy plays a novel role in promoting T cell survival in vivo. We found that autophagosomes form in primary T cells, and that the induction of autophagy is regulated in lymphocytes. To test the role of autophagy in T cells, we established two genetic models for the deletion of essential autophagy genes in primary T lymphocytes in vivo. In both Atg5-/- fetal liver chimeras and Atg7f/fLck-Cre mice, T cells developed in the thymus. However, we observed decreased numbers of mature peripheral T cells in naive mice. This reduction in peripheral autophagy-deficient T cell number was associated with an increase in apoptotic cell death. Although autophagy can contribute to the recycling of essential metabolic substrates, we found that autophagy-deficient T cells have intact resting metabolic function and die even in the presence of abundant growth-factor stimulation. A second important function for autophagy in cells is the removal of cytoplasmic material, which may include both proteins and whole organelles. We found that autophagy-deficient T cells have increased mitochondrial content by MitoTracker staining, mitochondrial DNA and mitochondrial proteins. This difference reflects an inability of autophagy-deficient T cells to clear mitochondrial content after cells exit the thymus, a process which normally occurs in autophagy-sufficient cells. Ongoing work seeks to understand the mechanisms by which autophagy-mediated T cell organelle homeostasis contributes to survival through the regulation of ROS production and intrinsic pathway apoptosis.