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Tailoring the functional Capacity of Cytotoxic T cells for future Therapies

Periodic Reporting for period 2 - ToCCaTa (Tailoring the functional Capacity of Cytotoxic T cells for future Therapies)

Reporting period: 2020-04-01 to 2021-09-30

What is the problem/issue being addressed?
CD8+ T cells pose enormous potential for prophylactic and therapeutic interventions against problematic infections and malignant tumours. A major obstacle to utilizing them effectively for therapeutic purposes is our limited understanding of the molecular foundation that enables CD8+ T cells to fulfil their pleotropic functions. Of particular importance are solution to induce large numbers of pathogen-specific T cells and effective strategies to adjust the functional capacity of T cells to the contrary needs of different diseases. For instance, large numbers of activated effector T cells are needed for treating cancer while resting memory T cells with high proliferative potential and tissues resident T cells are thought to limit the severity of viral infections. Similarly, the hypo-functional “exhausted” stage of T cells limits immune responses in chronic infections and cancer but the opposite outcome - less aggressive T cells with low tissue damaging potential - could be beneficial when vital organs such as lungs and liver are infected. Thus, to adjust qualitative aspects of T cell function is a current key challenge in the field.

- What are the overall objectives?
The instalment of defined functional profiles requires detailed knowledge of the molecular mechanisms and networks that guide T cell differentiation and strategies to manipulate them. Taking advantage of i) previously developed experimental systems to mimic disease related T cell phenotypes, ii) single cell gene expression assessments, iii) epigenetic characterizations, and 4i) high throughput strategies to alter gene expression, we seek to establish in vivo verified molecular dependencies and functional profiles. These unbiased studies will be complemented by hypothesis based functional assessments of previously identified candidate genes. Altogether, our studies are designed to discover new molecular targets, verified them in patient samples, and evaluate their therapeutic potential in disease-related large animal models.

- Why is it important for society?
The current SARS-CoV2 pandemic highlights the importance of increasing our knowledge of the mechanisms that protect us from viral infections. T cell-mediated immunity plays a role in primary pathogen clearance, while antibodies protect against re-infection and after vaccination. Although the primary function of T cells is to eliminate infected cells in tissues, it is well documented that excessive or overly strong T cell-mediated immunity can lead to severe tissue damage, a process known as immunopathology. Such excessive T-cell responses can cause significant damage to organs and are considered a major factor in severe COVID-19. To date, we have a very limited understanding of the processes that lead to such an overreaction of the immune system. With our project, we are investigating the mechanisms that control the extent and potential to cause immunopathology. We are therefore investigating key mechanisms that are critical during severe infection, including COIVD-19, and envision that our research will uncover potential therapeutic targets that could be useful in future pandemics.
Major findings of our project were published in Nature which underlines that we went beyond state of the art. Moreover, two further main publications are under preparation or were submitted already.