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Asymmetric fates: can autophagy rejuvenate memory by regulating T cell diversity?

  • Project No: KTPS-NC-12
  • Intake: 2021 KTPS-NC

PROJECT OUTLINE

Efficient T cell responses rely on diversity, characterized by the rise of effector and memory cells1. During ageing, the immune system gradually loses its capacity to generate heterogeneity. This leads to inefficient immune responses, which explains why elderly people are less able to fight infections/tumors and to respond to vaccines. The loss and functional impairment of stem-like cells, naïve and memory T cells, which are multi-potent and able to differentiate into a diverse progeny, is at the core of immune-senescence. There is cumulative evidence on the role of cell biological mechanisms in preserving T cell stemness. Autophagy, responsible for homeostatic degradation and recycling of cell cargo, is crucial for that2. We found that autophagy declines with age in T cells, which is detrimental for naïve and memory cells3. We have also observed that T cells from aged mice are unable to undergo asymmetric cell division (ACD, unpublished). ACD is a conserved mechanism to generate diversity, by endowing daughter cells with different fate determinants upon mitosis4-5. As both autophagy and ACD impact T cell differentiation and are impaired upon ageing, unravelling how they synergistically impact T cell memory formation is at the centre of this project. We have recently observed that autophagy is asymmetrically inherited in CD8 T cells, and that autophagy deficient cells lose certain layers of metabolic asymmetry, suggesting a possible role of autophagy as a regulator of ACD. This project will be dedicated to investigate the impact of autophagy loss in more detail. Our current working hypothesis is that autophagy is crucial for the establishment of asymmetric fates during T cell differentiation. Testing this hypothesis we aim to answer: (1) How is autophagic asymmetry built?, and (2) Does loss/impairment of autophagy impact asymmetric fates? To achieve these aims, we will take a global approach, investigating from cell biological mechanisms to physiological roles of autophagy/ACD in the establishment of lymphocyte stemness. We will submit wild type, autophagy knockout, and aged CD8 T cell progenies (daughter cells following first mitosis) to electron microscopy, proteomics and metabolomics analysis. This will provide us with an overview of autophagy-dependent asymmetries built during mitosis, and potentially allow us to identify novel cell fate-determinants. Since we already observed that one of the asymmetric layers lost in autophagy-deficient cells is composed by mitochondria, we will take advantage of a pioneering  murine model, in which aged organelles can be labelled in a time-restricted and permanent way. By not being subjected to new transcriptional/translational events, these tagged-organelles are perfect cargoes to study how segregation versus degradation (by autophagy) impact the establishment of asymmetric fates. We will further verify the physiological role of asymmetric degradation in a scenario of decreased autophagy, by using aged animals. We anticipate that this research will lead to the development of rejuvenation strategies to restore the ability of T cells to generate progenies endowed with distinct metabolic profiles and potential fates, by limiting the harmful effects of autophagy/ACD impairment. This will open opportunities for precise immunomodulation approaches, relevant in the context of regenerative medicine.

KEYWORDS

T cell memory, asymmetric fates, autophagy, immune system, ageing

TRAINING OPPORTUNITIES

Training will be provided in cell biological and immunological techniques (multi-parameter flow cytometry, cell sorting, high-resolution confocal microscopy), defining the proteome and metabolome (and related bioinformatics), and physiological assays to assess memory potential of T cells. You will attend regular seminars within the department and in the wider University. You will be expected to present data regularly in lab meetings and in departmental progress report seminars and in national and international conferences.  You will have the opportunity to work closely with collaborating groups interested in stem-like cells (Pekka Katajisto, University of Helsinki, Finland; Sten Eirik Jacobsen, WIMM (Oxford) and Karolinska Institute, Sweden; Annette Oxenius, ETHZ, Switzerland). Prof. Michael Dustin’s lab (KIR, Oxford) will provide collaborative support concerning T cell imaging. Mariana Borsa, senior postdoc in the lab, and an expert in T cell biology, will take on daily supervision. A core curriculum of lectures is offered in the first term to provide a solid foundation in a broad range of subjects including several aspects of immunity, epigenetics, translational approaches, data analysis, and statistics.

KEY PUBLICATIONS

  1. Kakaradov, B., Arsenio, J., Widjaja, C.E., He, Z., Aigner, S., Metz, P.J., Yu, B., Wehrens, E.J., Lopez, J., Kim, S.H., Zuniga, E.I., Goldrath, A.W., and Chang, J.T. Early transcriptional and epigenetic regulation of CD8(+) T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18, 422-432 (2017).
  2. Clarke, A. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells Nature Reviews Immunology, doi:10.1038/s41577-018-0095-2 (2018).
  3. Puleston, D. J., Zhang, H., Powell, T. J., Lipina, E., Sims, S., Panse, I., Watson, A. S., Cerundolo, V., Townsend, A. R., Klenerman, P. & Simon, A. K. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 3, doi:10.7554/eLife.03706 (2014).
  4. Borsa, M., Barnstorf, I., Baumann, N. S., Pallmer, K., Yermanos, A., Gräbnitz, F., Barandun, N., Hausmann, A., Sandu, I., Barral, Y., Oxenius, A. Modulation of asymmetric cell division as a mechanism to boost CD8 T cell memory. Science Immunol., eaav1730 (2019).
  5. Verbist, K.C., Guy, C.S., Milasta, S., Liedmann, S., Kaminski, M.M., Wang, R., and Green, D.R. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389-393 (2016).

THEMES

Immunology, Cell Biology, Ageing 

CONTACT INFORMATION

Contact: Prof Katja Simon, Kennedy Institute, University of Oxford

Email: katja.simon@kennedy.ox.ac.uk