Descrizione del progetto
Approfondimenti sulla staminalità dei linfociti della memoria
La memoria immunologica è in grado di fornire protezione a lungo termine contro le infezioni ricorrenti. Gli scienziati del progetto SCIMAP, finanziato dall’UE, hanno precedentemente dimostrato che le singole cellule T della memoria possono mantenere la memoria immunologica attraverso un meccanismo di autorinnovamento rilevato convenzionalmente nelle cellule staminali. Il campo di applicazione di SCIMAP è l’identificazione dell’esatto sottogruppo di cellule T che ospita tale staminalità nel corso delle infezioni croniche e la conferma della presenza di caratteristiche simili alle cellule staminali anche nelle cellule NK. Per raggiungere questo obiettivo, i ricercatori si avvarranno di codici a barre cellulari per tracciare la destinazione delle singole cellule T e NK in vivo e di imaging continuo a lungo termine per monitorarne lo sviluppo in vitro. Il progetto dispone del potenziale per identificare obiettivi molecolari e strategie immunoterapiche innovativi per il trattamento di infezioni o neoplasie.
Obiettivo
Almost two decades ago it was first proposed that immunological memory may depend on stem cell-like mechanisms, enabling individual antigen-specific T and B cells to generate progeny that contains short-lived effectors as well as long-lived memory cells. To test this capacity, I have in the past developed a stringent set of single cell-based approaches, which allowed me to show that single CD8+ and CD4+ T central memory cells harbour the capacity to self-renew and generate a diverse offspring of effector cells, but also, show immense variation in executing these essential functions upon activation.
Thus, even physiological immune responses to infection appear not to harness the full protective potential available in every antigen-specific lymphocyte. To better understand the regulatory principles underlying this single-cell derived variation, in the context of classical T-cell memory, T-cell exhaustion and memory-like NK cell responses, I developed novel fate mapping technologies such as ‘single-cell colour barcoding’ and ‘single-cell RNA barcoding’. I will now integrate these approaches with single-cell RNA sequencing, genetic reporter systems and continuous live-cell imaging, to answer three fundamental questions in immunobiology:
1) Do exhausted T-cell responses to chronic infection and adaptive-like immune responses of NK cells also rely on the stem cell-like potential of individual cells? 2) Do single-cell-derived T and NK cell families enter the memory or memory-like exhausted compartment on a direct road or through de-differentiation, after passing through an early effector state? And 3) how is the development of these T and NK cell families influenced by their founding members’ fundamental cellular properties, such as asymmetric cell-division, quorum sensing and cell-cycle speed? Answering these questions will help to identify new molecular targets and therapeutic strategies to enhance or reinvigorate protective immunity against infection or malignancy.
Campo scientifico
Parole chiave
Programma(i)
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
80333 Muenchen
Germania