Resolving molecular networks and dynamics of individual T cells in chronic infections
Final Report Abstract
Understanding and manipulating CD8 T cell exhaustion is of fundamental importance for improving T cell-based treatments against chronic infectious diseases and malignant tumours. Within the scope of this lead agency project, jointly funded by DFG and SNF, we have identified a novel master regulator of CD8 T cell exhaustion, the transcription factor TOX. This master regulator is required for the generation and long-term maintenance of exhausted CD8 T cell populations. Deletion of its DNA binding domain leads to a marked decline in the number of exhausted T cells induced by Cl13 infection—most pronounced in the TCF-1+ compartment of Tmex cells. Further on, we have shown that, in contrast to classical memory CD8 T cells, these Tmex cells do not require CD4 T cell help for their maintenance but only for their differentiation into more cytolytically-active effector subsets. Finally, we have used single-cell fate mapping to show that Tmex cells indeed harbour a stem-cell like capacity for self-renewal and multipotency but are imprinted early-on during chronic Cl13 infection with an exhausted differentiation program, which they faithfully maintain and pass on to their descendants even upon reactivation via acutely resolving Arm infection.
Publications
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(2019). Proliferation-competent Tcf1+ CD8 T cells in dysfunctional populations are CD4 T cell help independent. Proceedings of the National Academy of Sciences 116, 20070–20076
Kanev, K., Wu, M., Drews, A., Roelli, P., Wurmser, C., Hösslin, von, M., and Zehn, D.
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(2019). TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269
Alfei, F., Kanev, K., Hofmann, M., Wu, M., Ghoneim, H.E., Roelli, P., Utzschneider, D.T., Hoesslin, von, M., Cullen, J.G., Fan, Y., Zehn, D.
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(2020). Differential expansion of T central memory precursor and effector subsets is regulated by division speed. Nat Commun 11, 113
Kretschmer, L., Flossdorf, M., Mir, J., Cho, Y.-L., Plambeck, M., Treise, I., Toska, A., Heinzel, S., Schiemann, M., Busch, D.H., Buchholz V.R.
