Graduate Research Prize Winners Autumn 2014
After an undergraduate degree in Biology and a Masters in Immunology, I began my DPhil with Professor Katja Simon in the Weatherall Institute of Molecular Medicine. Katja’s lab is focused on a highly conserved intracellular pathway called autophagy. For 50 years autophagy had been accepted as a critical system for general cell homeostasis through its ability to degrade damaged organelles.
By the time I started my DPhil in 2011, cell biologists were awakening to the realization that autophagy was a crucial cog in cellular defence. Up to this point, observations had detailed how autophagy could remove intracellular bacteria in cells of the innate immune system.
However, I was more interested in the role that this ancient process had to play in the ultimate aim of the immune system – immunity. During my DPhil, I demonstrated how autophagy is an essential requirement for the formation of long-lasting immunity through its critical role in memory CD8+ T cell formation. Along with antibodies, memory CD8+ T cells provide essential long-term protection against viruses and other infections. In the wider context, autophagy had become heavily implicated in ageing, with experiments in lower organisms describing a strong link to longevity. In the immune system, dramatic changes take place during ageing that cumulatively result in poor immune responses to vaccination and infections in the elderly. With the population of over 65s scheduled to triple in size globally by 2050, this is a huge public health concern – a large population with high susceptibility to infection that we cannot vaccinate effectively. The issue is that we don't know what drives these deleterious changes in the immune system with old age. A central hypothesis is that the immune system becomes heavily preoccupied attempting to keep herpesviruses such as CMV in check, not leaving much “room” left over to respond to other infections. However, this didn't stack up as individuals uninfected with herpesviruses still responded poorly to vaccination.
Seeing as autophagy had been implicated in ageing at the whole organism level, we wondered if was implicated at the cellular level in the immune system. Indeed, we went on to show how autophagy levels fall in the immune system with age. This begs the question: if autophagy levels could be restored in the elderly immune system, might one be able to restore effective immune responses to vaccination also? Using an over-looked class of compounds called polyamines (shown to boost autophagy) I showed it was possible to rejuvenate immune responses to vaccination in elderly mice, returning them to the same levels observed in young animals. Unexpectedly, these experiments were highlighted in articles in The Daily Mail and The Times. More importantly however, they expand our knowledge as to how immune memory wanes with age and identify a new pathway and class of compounds able to restore immunity in the aged. As a post-doc, I hope to explore further the biology of polyamines and their potential to form a novel class of immune adjuvants able to be incorporated into future vaccine formulations for the elderly and beyond.
Puleston, D.J., Zhang, H., Powell, T. J et al. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3:e03706 (2014).
Puleston, D.J. and Simon, A.K. Autophagy in the Immune system. Immunology, 141: 1-8 (2014).
Jabir, M. S., Hopkins, L., Ritchie, N. D., Ullah, I. Puleston, D. J. et al. TRIF Cleavage by Caspase-1 Inhibits Autophagy and β-Interferon Production During Infection with Pseudomonas aeruginosa. Cell Host Microbe 15:214-227 (2014).
Sian Henson, Alessio Lanna, Natalie E. Riddell, Daniel J. Puleston, Alexander Scarth Watson, Anna Katharine Simon, and Arne N. Akbar. Altered bioenergetics in senescent human CD8+ T cells is regulated by m38 MAPK signaling. Journal of Clinical Investigation 124(9): 4004–4016 (2014).