Simon Group | Autophagy in the Immune System
Autophagy is a major degradation pathway in the cell. While the ubiquitin/proteasome system degrades proteins, autophagy degrades bulk cytoplasmic material. Autophagosomes have been shown to engulf whole organelles, such as mitochondria, lipid droplets and Golgi and as a consequence autophagy impacts on metabolism, apoptosis, differentiation, cell cycle and cell fate decisions in the cell.
Over the last decade we have studied the role of autophagy in the development and function of hematopoietic and immune cells using in vivo models and in vitro techniques applied to human samples.
We pioneered a technique detecting autophagy in primary cells and showed a decrease in autophagy levels in ageing T lymphocytes (Phadwal et al, Autophagy 2012). Our previous research also reveals that red blood cells need autophagy to degrade mitochondria for their final maturation (Mortensen et al, PNAS 2010). Hematopoietic stem cells require autophagy for their maintenance (Mortensen, J Exp Med et al, 2011), and in the absence of autophagy, we observe a mild pre-leukemic phenotype. We measured low levels of autophagy in human acute myeloid leukemia samples (Watson et al, Cell Death Discovery 2015). Autophagy is required for neutrophil differentiation providing free fatty (Riffelmacher et al, Immunity 2017). The survival/ maintenance of memory T cells is also reliant on autophagy. We find that inducing autophagy in the aged T cells with a drug (spermidine) reverses an inefficient memory T cell response to influenza vaccination (Puleston et al, elife, 2014). Re-introducing autophagy also improves B cell responses in older mice and adults. We have discovered a novel pathway, controlling autophagy translationally, that is decreased with age (Zhang et al, Mol Cell 2019). We also found that B2 cells require autophagy but not B1 cells (Clarke et al, JEM 2018).
We are now trying to understand the role of autophagy in immune cell fate mechanistically, by identifying the autophagosomal cargo in vivo and during cell division, and how autophagy in the microenvironment impacts on immune cells. With this knowledge we are aiming to identify novel drug targets and drugs to be used in hematopoietic malignancies, regenerative medicine and vaccination of older adults.