|ERC Starting Grant 2018|
|Name of the Principal Investigator (PI)||Ondřej Štěpánek|
|Name of the PI’s host institution for the project||Institute of Molecular Genetics of the Czech Academy of Sciences|
|Proposal duration in months||60 (01/2019 – 12/2023)|
T cells have a central role in most adaptive immune responses, including immunity to infection, cancer, and autoimmunity. Increasing evidence shows that even resting steady-state T cells form many different subsets with unique functions. Variable level of self-reactivity and previous antigenic exposure are most likely two major determinants of the T-cell diversity. However, the number, identity, and biological function of steady-state T-cell subsets are still very incompletely understood. Receptors to ligands from TNF and B7 families exhibit variable expression among T-cell subsets and are important regulators of T-cell fate decisions. We hypothesize that pathways triggered by these receptors substantially contribute to the functional diversity of T cells. The FunDiT project uses a set of novel tools to systematically identify steady-state CD8+ T cell subsets and characterize their biological roles.
(1) Identification of CD8+ T cell subsets. We will identify subsets based on single cell gene expression profiling. We will determine the role of self and foreign antigens in the formation of these subsets and match corresponding subsets between mice and humans.
(2) Role of particular subsets in the immune response. We will compare antigenic responses of particular subsets using our novel model allowing inducible expression of a defined TCR. The activity of T-cell subsets in three disease models (infection, cancer, autoimmunity) will be characterized.
(3) Characterization of key costimulatory/inhibitory pathways. We will use our novel mass spectrometry-based approach to identify receptors and signaling molecules involved in the signaling by ligands from TNF and B7 families in T cells.
The results will provide understanding of the adaptive immunity in particular disease context and resolve longstanding questions concerning the roles of T-cell diversity in protective immunity and tolerance to healthy tissues and tumors.
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 802878).
Draberova H, Janusova S, Knizkova D, Semberova T, Pribikova M, Ujevic A, Harant K, Knapkova S, Hrdinka M, Fanfani V, Stracquadanio G, Drobek A, Ruppova K, Stepanek O, Draber P: Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop. EMBO J 2020. [doi]
Horkova V, Drobek A, Mueller D, Gubser C, Niederlova V, Wyss L, King CG, Zehn D, Stepanek O: Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells. Cell Rep 2020 30(5): 1504-1514.e7. [doi]
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