Impaired Autophagy, Defective T Cell Homeostasis, and a Wasting Syndrome in Mice with a T Cell–Specific Deletion of Vps34
- 15 May 2013
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 190 (10), 5086-5101
- https://doi.org/10.4049/jimmunol.1202071
Abstract
Autophagy plays a critical role in multiple aspects of the immune system, including the development and function of T lymphocytes. In mammalian cells, the class III PI3K vacuolar protein sorting (Vps)34 is thought to play a critical role in autophagy. However, recent studies have cast doubt on the role of Vps34 in autophagy, at least in certain cell types. To study the effects of Vps34 on autophagy in T lymphocytes, we generated mice that selectively lack Vps34 in the T cell lineage. Vps34 ablation in T cells caused profound defects in autophagic flux, resulting in accumulation of cellular organelles and apoptosis. These animals exhibited normal intrathymic development of conventional T cells, but they were profoundly impaired in the intrathymic development of invariant NKT cells. In peripheral organs, T cell–specific ablation of Vps34 had a profound impact on T cell homeostasis and function. Furthermore, aged animals developed an inflammatory wasting syndrome characterized by weight loss, intestinal inflammation, and anemia. Consistent with this phenotype, Vps34 was required for the peripheral maintenance and function of CD4+Foxp3+ regulatory T cells. Collectively, our study reveals a critical role for Vps34 in autophagy and for the peripheral homeostasis and function of T lymphocytes.Keywords
This publication has 55 references indexed in Scilit:
- Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasisProceedings of the National Academy of Sciences of the United States of America, 2012
- Sam50 Functions in Mitochondrial Intermembrane Space Bridging and Biogenesis of Respiratory ComplexesMolecular and Cellular Biology, 2012
- Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver functionProceedings of the National Academy of Sciences of the United States of America, 2012
- Essential role of Mediator subunit Med1 in invariant natural killer T-cell developmentProceedings of the National Academy of Sciences of the United States of America, 2011
- Autophagy in immunity and inflammationNature, 2011
- Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathwayProceedings of the National Academy of Sciences of the United States of America, 2010
- Coordination of membrane events during autophagy by multiple class III PI3-kinase complexesThe Journal of cell biology, 2009
- Enhancing CD8 T-cell memory by modulating fatty acid metabolismNature, 2009
- CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune systemCurrent Opinion in Immunology, 2008
- A critical role for the autophagy gene Atg5 in T cell survival and proliferationThe Journal of Experimental Medicine, 2006