Reciprocal effects of rab7 deletion in activated and neglected T cells

Autophagy. 2013 Jul;9(7):1009-23. doi: 10.4161/auto.24468. Epub 2013 Apr 15.

Abstract

Mouse models lacking proteins essential for autophagosome formation have demonstrated that autophagy plays a critical role in T cell development and activation. To better understand the function of autophagy in quiescent and activated lymphocytes, we have generated a mouse deficient in rab7 selectively in T cells and compared the effects of blocking autophagy at an early (atg5(-/-)) or late (rab7(-/-)) stage on T cell biology. rab7(-/-) murine embryonic fibroblasts (MEFs) and T cells generated from these mice exhibit a profound block in autophagosome degradation and are as sensitive as atg5(-/-) cells to extracellular nutrient limitation. Rab7(flox/flox)CD4-Cre(+) mice lacking the RAB7 protein in both CD4 and CD8 T cells had reduced numbers of peripheral T cells, but this defect was not as severe as in Atg5(flox/flox)CD4-Cre(+) mice despite efficient rab7 deletion and inhibition of autophagic flux. This difference may stem from the reduced ROS generation and enhanced survival of rab7(-/-) T cells compared with wild-type and atg5(-/-) T cells in the absence of cytokine stimulation. rab7(-/-) and atg5(-/-) T cells exhibited similar defects in proliferation both following antibody-mediated T cell receptor (TCR) cross-linking and using a more physiologic activation protocol, allogeneic stimulation. Interestingly, autophagy was not required to provide building blocks for the upregulation of nutrient transporter proteins immediately following activation. Together, these studies suggest that autophagosome degradation is required for the survival of activated T cells, but that loss of rab7 is better tolerated in naïve T cells than the loss of atg5.

Keywords: ATG5; RAB7; T cells; autophagy; growth factor withdrawal; lysosomal fusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Autophagy
  • Autophagy-Related Protein 5
  • Biomarkers / metabolism
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Deletion*
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Phagosomes / metabolism
  • Phenotype
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes / metabolism*
  • rab GTP-Binding Proteins / deficiency*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Biomarkers
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • rab7 protein
  • rab GTP-Binding Proteins