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, Kristiyan; Wu, Ming; Drews, Antar; Roelli, Patrick; Wurmser, Christine; von Hösslin, Madlaina & Zehn, Dietmar
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(2019). TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269
Alfei, Francesca; Kanev, Kristiyan; Hofmann, Maike; Wu, Ming; Ghoneim, Hazem E.; Roelli, Patrick; Utzschneider, Daniel T.; von Hoesslin, Madlaina; Cullen, Jolie G.; Fan, Yiping; Eisenberg, Vasyl; Wohlleber, Dirk; Steiger, Katja; Merkler, Doron; Delorenzi, Mauro; Knolle, Percy A.; Cohen, Cyrille J.; Thimme, Robert; Youngblood, Benjamin; ... & Zehn, Dietmar
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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, Lorenz; Flossdorf, Michael; Mir, Jonas; Cho, Yi-Li; Plambeck, Marten; Treise, Irina; Toska, Albulena; Heinzel, Susanne; Schiemann, Matthias; Busch, Dirk H. & Buchholz, Veit R.
