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Mapping the life histories of T cells

Final Report Summary - LIFE-HIS-T (Mapping the life histories of T cells)

Our immune system protects us from infection with pathogens and can also control the growth of a number of human cancers. An understanding of the regulation of immune cell function, and in particular the function of the T cell subset of the immune system, has resulted in the development of a substantial number of novel therapies, including the cancer immunotherapeutics that now form standard of care for e.g. melanoma and lung cancer. A major limitation of much of the prior work on T cell function has been that the in vivo development and differentiation of cells was followed at the bulk level. For instance, whether individual naïve T cells generated the same or different offspring once activated had remained unclear. To answer this type of questions, this project has developed and exploited technology to follow individual T cells and other immune cells over time. From the work, a number of conclusions can be drawn. First, the T cell-based immune system is very much an ‘unequal society’, in which a small number of T cells creates the vast majority of cellular output, and with most other cells only contributing little (1-3). Second, a similar heterogeneity at the single cell level is also observed in different types of hematopoietic progenitors (4,5). Third, we have also analyzed the function of the tissue-resident memory T cells that are considered a first line of defense against renewed infections. Through this work, we demonstrated that tissue-resident memory T cells carry out this function by continuously patrolling the tissue site for signs of renewed infection (6). Furthermore, we demonstrated that the protective effect of tissue-resident memory T cells is at least partially based on their ability to induce the expression of anti-viral/ anti-bacterial molecules within the surrounding tissue, at the moment the tissue-resident memory T cells sense an incoming pathogen.

In addition to the improved biological understanding of fundamental aspects of the functioning of our immune system, this project has yielded a number of new technological approaches (reviewed in 3, 8) that may be applied in other biological fields to study the behavior of individual cells, the fundamental unit of life.

1. Gerlach et al. Science 2013
2. Rohr et al. Trends Immunol. 2014
3. Buchholtz et al. Ann. Rev . Immunol. 2016
4. Naik et al. Nature 2013
5. Perie et al. Cell 2015
6. Ariotti et al. Proc. Natl. Acad. Sci. USA 2012
7. Ariotti et al Science 2014
8. Hoekstra et al. Trends Immunol 2015